8-(3-Biaryl)phenylquinoline phosphodiesterase-4 inhibitors

ABSTRACT

Novel substituted 8-phenylquinolines represented by Formula (I), wherein the phenyl group at the 8-position contains an aryl or heteroaryl substituent in the meta position, are PDE4 inhibitors.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that are substituted8-phenylquinolines. In particular, this invention is directed tosubstituted 8-phenylquinolines which are phosphodiesterase-4 inhibitorswherein the phenyl group at the 8-position contains a meta aryl orheterocyclic group.

2. Related Background

Hormones are compounds that variously affect cellular activity. In manyrespects, hormones act as messengers to trigger specific cellularresponses and activities. Many effects produced by hormones, however,are not caused by the singular effect of just the hormone. Instead, thehormone first binds to a receptor, thereby triggering the release of asecond compound that goes on to affect the cellular activity. In thisscenario, the hormone is known as the first messenger while the secondcompound is called the second messenger. Cyclic adenosine monophosphate(adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is knownas a second messenger for hormones including epinephrine, glucagon,calcitonin, corticotrophin, lipotropin, luteinizing hormone,norepinephrine, parathyioid hormone, thyroid-stimulating hormone, andvasopressin. Thus, cAMP mediates cellular responses to hormones. CyclicAMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′,5′cyclic nucleotides to 5′ nucleoside monophosphates, thereby terminatingcAMP second messenger activity. A particular phosphodiesterase,phosphodiesterase-4 (“PDE4”, also known as “PDE-IV”), which is a highaffinity, cAMP specific, type IV PDE, has generated interest aspotential targets for the development of novel anti-asthmatic andanti-inflammatory compounds. PDE4 is known to exist as at lease fourisoenzymes, each of which is encoded by a distinct gene. Each of thefour known PDE4 gene products is believed to play varying roles inallergic and/or inflammatory responses. Thus, it is believed thatinhibition of PDE4, particularly the specific PDE4 isoforms that producedetrimental responses, can beneficially affect allergy and inflammationsymptoms. It would be desirable to provide novel compounds andcompositions that inhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in C.Burnouf et al., (“Burnouf”), Ann. Rep. In Med. Chem.,33:91-109(1998). B.Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996);M. J. Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S. B.Christensen et al., J.Med. Chem., 41:821-835(1998); and Burnouf describethe wide variation of the severity of the undesirable side effectsexhibited by various compounds. As described in M. D. Houslay et al.,Adv. In Pharmacol., 44:225-342(1998) and D.Spina et al., Adv. InPharmacol., 44:33-89(1998), there is great interest and research oftherapeutic PDE4 inhibitors.

International Patent Publication WO9422852 describes quinolines as PDE4inhibitors. U.S. Pat. No. 6,410,563 describes 8-arylquinoline PDE4inhibitors.

A. H. Cook, et al., J.Chem. Soc., 413-417(1943) describesgamma-pyridylquinolines. Other quinoline compounds are described in KeiManabe et al., J.Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al.,J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am.Chem Soc., 114(17):6940-6941(1992).

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541describesubstituted benzoylguanidine sodium channel blockers, U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.

U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958,5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593,5,891,896, and International Patent Publication WO 95/35283 describePDE4 30 inhibitors that are tri-substituted aryl or heteroaryl phenylderivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that arestyryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitorsthat are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S.Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substitutedphenyl derivatives. International Patent Publication WO 96/00215describes substituted oxime derivatives useful as PDE4 inhibitors. U.S.Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl andalkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted8-phenylquinolines that are PDE4 inhibitors, wherein the phenyl group atthe 8-position is substituted by an aryl or heterocyclic group in themeta position. This invention also provides a pharmaceutical compositionwhich includes an effective amount of the novel substituted8-phenylquinoline and a pharmaceutically acceptable carrier. Thisinvention further provides a method of treatment in mammals of, forexample, asthma, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), eosinophilic granuloma, psoriasis and other benign ormalignant proliferative skin diseases, endotoxic shock (and associatedconditions such as laminitis and colic in horses), septic shock, celiacsprue, ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, chronic obstructive pulmonary disease in animals,diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernalconjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis,neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease,hypersecretion of gastric acid, bacterial, fungal or viral inducedsepsis or septic shock, inflammation and cytokine-mediated chronictissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting,depression, memory impairment, tumour growth and cancerous invasion ofnormal tissues by the administration of an effective amount of the novelsubstituted 8-phenylquinoline.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the invention is directed to compounds represented byFormula (I):

and pharmaceutically acceptable salts, wherein

-   -   S₁, S₂, and S₃ are independently    -   1. H,    -   2. —OH,    -   3. halogen,    -   4. —C₁-C₆alkyl,    -   5. —O—C₁-C₆alkyl optionally substituted with 1, 2 or 3 halogens,        or    -   6. —CN;    -   R₁ is 1. —(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl) group, optionally        substituted with 1, 2 or 3 substituents; wherein each        substituent is independently a halogen, —OH and —CN,    -   2. —C(O)—O-aryl,    -   3. —C(O)—NH-aryl,    -   4. —C(O)—NH-heterocycle or N-oxide thereof,    -   5. —C(O)—NH-C₁-C₆alkyl,    -   6. —C(O)—NH-cycloC₃-C₆alkyl,    -   7. —C₁-C₆alkyl, optionally substituted with 1 to 6 halogens and        1 hydroxy,    -   8. COOH,    -   9. —C₁-C₆alkyl-COOH,    -   10. —O—C₁-C₆alkyl,    -   11. -cycloC₃-C₆alkyl,    -   12. —C₃-C₆alkyl-heterocycle,    -   13. aryl,    -   14. heterocycle,    -   15. carbonyl,    -   16. carbamoyl, or    -   17. —SO_(n)—(C₁-C₆alkyl);    -   each n is independently 0, 1, or 2;    -   Ar₁ and Ar₂ are each independently an aryl or heterocycle or an        N-oxide thereof;    -   R₂ is    -   1. Hydrogen,    -   2. aryl optionally substituted with 1, 2 or 3 substituents        selected from halogen,    -   3. heterocycle optionally substituted with 1, 2 or 3 halogens,    -   4. —C₁-C₆alkyl optionally substituted with 1, 2 or 3        substituents selected from hydroxy and halogen,    -   5. —COOH,    -   6. 1, 2 or 3 halogens,    -   7. —SO_(n)—(C₁-C₆alkyl),    -   8. —N(H)—S(O)_(n)—C₁-C₆alkyl,    -   9. —O—C₁-C₆alkyl substituents each optionally substituted with        1, 2 or 3 halogens,    -   10. —C(O)—N(H)—C₃-C₆cycloalkyl, or    -   11. —C(O)—C₁-C₆alkyl;    -   R₃ is    -   1. Hydrogen,    -   2. —C₁-C₆alkyl optionally substituted with hydroxy,        —(O)_(n)C₁-C₆alkyl, heterocycle, or 1, 2, 3, 4, 5 or 6 halogens,    -   3. aryl or C₆-C₁₂cycloalkyl optionally substituted with phenyl,        —C₁-C₆alkyl, —S(O)_(n)C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl, —COOH,        hydroxy-C₁-C₆alkyl- or 1, 2 or 3 halogens,    -   4. heterocycle or optionally substituted with 1, 2 or 3        substituents independently selected from phenyl, halogen,        C₁-C₆alkyl, hydroxyC₁-C₆alkyl, —COOH, —C(O)—O—C₁-C₆alkyl,    -   5. amino,    -   6. —C(O)—O—C₁-C₆allyl,    -   7. —C₁-C₆alkyl-O-phenyl optionally substituted with 1, 2 or 3        halogens,    -   8. —C₁-C₆alkyl-phenyl optionally substituted with 1 or 2        substituents selected from hydroxy and halo,    -   9. —COOH,    -   10. Halogen,    -   11. —SO_(n)—(C₁-C₆alkyl),    -   12. —N(H)—S(O)_(n)—C₁-C₆alkyl optionally substituted with 1, 2        or 3 halogen,    -   13. —N(H)—C(O)—C₁-C₆alkyl,    -   14. —N(H)-heterocycle optionally substituted with 1, 2 or 3        halogens,    -   15. —N(H)-aryl optionally substituted with 1, 2 or 3 halogens,    -   16. —N(H)—C₁-C₆alkyl optionally substituted with 1, 2 or 3        halogens,    -   17. —C(O)—N(H)—C₁-C₆alkyl optionally substituted with 1, 2 or 3        halogens,    -   18. —C(O)—NH—C₃-C₆cycloalkyl,    -   19. —O—C₁-C₆alkyl optionally substituted with 1, 2 or 3 halogens        or phenyl optionally substituted with 1, 2, or 3 halogen;    -   R₄ is    -   1. H,    -   2. Halogen,    -   3. —CN    -   4. —C₁-C₆alkyl,    -   5. —O—C₁-C₆alkyl optionally substituted with 1, 2 or 3 halogens,    -   6. —C₁-C₆alkyl-phenyl with phenyl optionally substituted with        halogen, or    -   7. Oxo.

Within this first aspect is the genus of compounds and pharmaceuticallyacceptable salts thereof, wherein

-   -   Ar₁ is pyridine or pyridinone or an N-oxide thereof.

Within this genus is the sub-genus of compounds and pharmaceuticallyacceptable salts thereof, wherein

-   -   Ar₂ is phenyl, oxadiazole or thiadiazole, tetrazole.

Within this sub-genus is the class of compounds and pharmaceuticallyacceptable salts thereof, wherein

-   -   R₁ is —(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl); and    -   R₂ is —SO_(n)—C₁-C₆alkyl.

Also within this first aspect, there is a genus of compounds andpharmaceutically acceptable salts thereof, wherein

-   -   Ar₁ is phenyl.

Within this genus there is a sub-genus of compounds and pharmaceuticallyacceptable salts thereof, wherein

-   -   Ar₂ is phenyl, oxadiazole, thiadiazole, tetrazole, pyridine or        pyridinone or an N-oxide thereof.

Within this sub-genus there is a class of compounds and pharmaceuticallyacceptable salt thereof, wherein

-   -   R₁ is —(C₁-C₆alkyl)—SO_(n)—(C₁-C₆alkyl); and    -   R₂ is —SO_(n)—C₁-C₆alkyl.

Also within the first aspect there is a genus of compounds andpharmaceutically acceptable salts thereof, wherein

-   -   Ar₁ is thiazole or oxazole.

Within this genus there is a sub-genus of compounds and pharmaceuticallyacceptable salts thereof, wherein

-   -   Ar₂ is phenyl, pyridine or pyridinone or an N-oxide thereof.

Within this sub-genus of compounds there is a class of compounds andpharmaceutically acceptable salts thereof, wherein

-   -   R₁ is —(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl); and    -   R₂ is —SO_(n)—C₁-C₆alkyl.

Also within the first aspect there is a genus of compounds of Formula Ia

and a pharmaceutically acceptable salts thereof, wherein:

Ar₁ is phenyl, pyridine, pyridinone, pyrimidyl, thiophene, thiazole,triazole, tetrazole, oxazole, thienodiazole, pyridodiazole,imidazothiazole or quinoxaline or an N-oxide thereof; and

Ar₂ is phenyl, pyridine, pyridinone, oxadiazole, tetrazole orthiadiazole or an N-oxide thereof.

Within this genus of compounds of Formula Ia there is a sub-genus ofcompounds and pharmaceutically acceptable salts thereof, wherein:

R₂ is phenyl, —COOH, —C₁-C₆alkyl, —C₁-C₆alkoxy, mono ordi-halo-C₁-C₆alkoxy, -hydroxyC₁-C₆alkyl, or —SO_(n)—(C₁-C₆alkyl) or 1, 2or 3 halogens.

Within this sub-genus there is a class of compounds of Formula Ia andpharmaceutically acceptable salt thereof, wherein:

R₃ is Hydrogen, amino, biphenyl,N-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-yl,N-(tert-butoxycarbonyl)azetidin-3-yl,N-(tert-butoxycarbonyl)pyrrolidin-3-yl, 3chloro-4-fluorophenyl,4-chlorophenoxymethyl, 2-chlorophenyl, 4-chlorophenyl, ethoxycarbonyl,furan-2-yl, furan-3-yl, imidazol-2-yl, indan-1-yl, indan-2-yl,1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl,1H-indol-6-yl, 1H-indol-7-yl, isoquinolin-1-yl, isoquinolin-4-yl,isoquinolin-5-yl, isoquinolin-8-yl, isoxazol-3-yl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, methyl,1-methyl-1Hpyrazol-3-yl, 1-methyl-1Hpyrazol-4-yl,1-methyl-1Hpyrazol-5-yl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-methylpyridin-5-yl, methylsulfonylmethyl, 2-methylsulfonylphenyl,3-methylsulfonylphenyl, 4-methylsulfonylphenyl, morpholin-4-ylmethyl,phenyl, pyrazinyl, 1H-pyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridinyl, pyridin-2-yl N-oxide, pyridin-3-yl N-oxide, pyridin-4ylN-oxide, 3-pyridinylmethyl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, quinolin-4-yl, quinolin-5-yl, quinolin-8-yl,5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl,5,6,7,8-tetrahydro-5H-benzo[a][7]annulen-5-yl,5,6,7,8-tetrahydro-5H-benzo[a][7]annulen-6-yl, tetrahydrofuran-2-yl,1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4tetrahydronaphthalen-2-yl,1,3-thiazol-2-yl, 1,3-thiazol-5-yl, thiophen-2-yl and thiophen-2-yl,3-(propan-2-ol)-phenyl, 4(propan-2-ol)-phenyl, propan-2-ol,hexafluoropropan-2-ol.

Also within the genus of compounds of Formula Ia there is the sub-genusof compounds and pharmaceutically acceptable salts thereof, wherein:

-   -   Ar₁ is thiazole;    -   Ar₂ is phenyl; and    -   R₂ is —SO₂—C₁-C₆alkyl or halogen or C₁-C₆alkyl optionally        substituted with hydroxy or 1-3 halogens.

Within this sub-genus there is the class of compounds andpharmaceutically acceptable salts thereof, wherein:

-   -   R₃ is    -   1. Hydrogen,    -   2. —C₁-C₆alkyl optionally substituted with hydroxy,        —S(O)_(n)C₁-C₆alkyl, or 1-6 halogens.

For Example, R₃ may be propan-2-ol, hexafluoropropan-2-ol, such thatR₃—Ar may be 3-(propan-2-ol)-phenyl or 3-methylsulfonylphenyl.

Also within the genus of compounds of Formula Ia there is the sub-genusof compounds and pharmaceutically acceptable salts thereof, wherein

-   -   Ar₁ is pyridine or an N-oxide thereof;    -   Ar₂ is oxadiazole; and    -   R₂ is    -   1. —C₁-C₆alkyl optionally substituted with hydroxy,        —S(O)_(n)C₁-C₆alkyl, or 1-3 substituents halogens,    -   2. —N(H)—C(O)—C₁-C₆alkyl,    -   3. COOH, or    -   4. —C(O)—NH—C₃-C₆cycloalkyl.

Within this sub-genus of compounds of Formula Ia there is a class ofcompounds and pharmaceutically and acceptable salts thereof wherein:

-   -   R₃ is hydrogen.

Illustrating the invention are:

-   8-(3-{2-(3-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-[4-(methylsulfonyl)phenyl]-2-(1-oxidopyridin-4-yl)-1,3-thiazol-5-yl]phenyl}quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-(4-(methylsulfonyl)phenyl]-2-(1-oxidopyridin-3-yl)-1,3-thiazol-5-yl]phenyl}quinoline,-   2-(3-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}phenyl)propan-2-ol,-   3-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}benzoic    acid,-   2-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,-   N-cyclopropyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-    (methylsulfonyl)phenyl]-1,3-thiazole-2-carboxamide,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(6-methyl-1-oxidopyridin-3-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,-   2-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-methyl-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}phenyl)quinoline,-   2-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol,-   1,1,1-trifluoro-N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}methanesulfonamide,-   2-[5-(3-(6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-pyridin-3-yl-1,3-thiazol-2-yl]propan-2-ol,-   2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-(1-oxidopyridin-3-yl)-1,3-thiazol-2-yl]propan-2-ol,-   1-(4-chlorophenyl)-1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}ethanol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]thien-2-yl)phenyl)quinoline,-   1-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1′-terphenyl-4-yl)ethanone,-   2-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)propan-2-ol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-oxidopyridin-3-yl]phenyl)quinoline,-   5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6-[4-(methylsulfonyl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl}phenyl)quinoline-   [3-{(6-1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}4″-(methylthio)-1,1′:2′,1″-terphenyl-4′-yl]methanol,-   [3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]methanol,-   2-[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]propan-2-ol,-   3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-carboxylic    acid,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   8-{3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline,-   3,-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl4-carboxylic    acid,-   2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]pyrazin-2-yl}phenyl)quinoline,-   5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,-   1-methyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,-   8-(3-{6-methoxy-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-(3-{6-(difluoromethoxy)-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-(3-{6-[(4-fluorobenzyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl)phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   1-(4-fluorobenzyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,-   5-(4-fluorophenyl)-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one,-   5-(4-fluorophenyl)-1-methyl-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl)phenyl)pyridin-2(1H)-one,-   8-{3-[3-(4fluorophenyl)-6-methoxypyridin-2-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   and pharmaceutically acceptable salts thereof.

Further illustrating the invention are the compounds of the Formula:

wherein R is selected from the group consisting of Amino 2-biphenyl3-biphenyl N-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-ylN-(tert-butoxycarbonyl)azetidin-3-ylN-(tert-butoxycarbonyl)pyrrolidin-3-yl 3-chloro-4-fluorophenyl4-chlorophenoxymethyl 2-chlorophenyl 4-chlorophenyl Ethoxycarbonylfuran-2-yl furan-3-yl imidazol-2-yl indan-1-yl indan-2-yl 1H-indol-2-yl1H-indol-3-yl 1H-indol-4-yl 1H-indol-5-yl 1H-indol-6-yl 1H-indol-7-ylIsoquinolin-1-yl Isoquinolin-4-yl Isoquinolin-5-yl Isoquinolin-8-ylisoxazol-3-yl 3-methoxycarbonylphenyl 4-methoxycarbonylphenyl Methyl1-methyl-1H-pyrazol-3-yl 1-methyl-1H-pyrazol-4-yl1-methyl-1H-pyrazol-5-yl 2-methylphenyl 3-methylphenyl 4-methylphenyl2-methylpyridin-5-yl Methylsulfonylmethyl 2-methylsulfonylphenyl3-methylsulfonylphenyl 4-methylsulfonylphenyl morpholin-4-ylmethylPhenyl Pyrazinyl 1H-pyrazol-3-yl pyridin-2-yl pyridin-3-yl pyridin-4-yl3-pyridinylmethyl pyrimidin-2-yl pyrimidin-4-yl pyrimidin-5-ylquinolin-4-yl quinolin-5-yl quinolin-8-yl5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl6,7,8,9-tetrahydro-5H-benzo[a][7]annulen-5-yl6,7,8,9-tetrahydro-5H-benzo[a][7]annulen-6-yl Tetrahydrofuran-2-yl1,2,3,4-tetrahydronaphthalen-1-yl 1,2,3,4-tetrahydronaphthalen-2-yl1,3-thiazol-2-yl 1,3-thiazol-5-yl thiophen-2-yl thiophen-3-ylAnd pharmaceutically accpetable salts thereof.

Further illustrating the invention are:

-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[3-(methylsulfonyl)phenyl]-4-phenyl-1,3-thiazol-5-yl}phenyl)quinoline,-   2-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,-   2-[4-(4-fluorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,-   8-{3-[4-(4-chlorophenyl)-2-quinolin-5-yl-1,3-thiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   2-{3-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,-   2-{3-[4-(3-chlorofluorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,-   2-{3-[4-[3,4-bis(difluoromethoxy)phenyl]-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,-   N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide,-   N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-[4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}pyridin-4-amine,-   2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-pyridin-4-yl-1,3-thiazol-2-yl]propan-2-ol,-   2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4(1-oxidopyridin-4-yl)-1,3-thiazol-2-yl]propan-2-ol,-   2-[5-(4-chlorophenyl)-4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,-   2-{3-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,    and-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(1H-tetraazol-5-yl)pyridin-3-yl]phenyl}quinoline,-   and pharmaceuticaly acceptable salts thereof.

Further illustrating the invention are:

-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[3-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[2-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3-(1-oxido-5-phenylpyridin-3-yl)phenyl]quinoline,-   8-{3-[5-(3,5-dichlorophenyl)-1-oxidopyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-{3-[5-(3,4-dimethoxyphenyl)-1-oxidopyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxidopyridin-3-yl]phenyl}quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxidopyridin-3-yl]phenyl}quinoline,-   8-(3-[6-(benzyloxy)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-2-yl]phenyl}quinoline,-   1-(4-chlorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one,-   N-isopropyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:2′,1″-terphenyl-3-yl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[4″-(methylthio)-1,1′:2′,1″-terphenyl-3-yl]quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[2′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-yl]quinoline,-   methyl    3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-carboxylate,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:4′,1″-terphenyl-3-yl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:3′,1″-terphenyl-3-yl)quinoline,-   2-[5-(3′-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′-biphenyl-2-yl)-1,3-thiazol-2-yl]propan-2-ol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3′-(1-oxidopyridin-4-yl)-1,1′-biphenyl-3-yl]quinoline,-   and pharmaceutically acceptable salts thereof.

Further illustrating the invention are:

-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[3-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline,-   8-[4′,5′-difluoro-4″-(methylthio)-1,1′:2′,1″-terphenyl-3-yl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-[4′,5′-difluoro-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3-yl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-(4″-fluoro-1,1′:2′,1″-terphenyl-3-yl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   6,7-dichloro-2-(3-6{-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline,-   2-(4-chlorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,-   2-{4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]phenyl}propan-2-ol,-   2-[3,4-bis(difluoromethoxy)phenyl]-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,-   4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]benzoic    acid,-   N-cyclopropyl-4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]benzamide,-   2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-(4-methylphenyl)quinoxaline,-   2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-phenylquinoxaline,-   2-(4-fluorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,-   2-{4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyrazin-2-yl]phenyl}propan-2-ol,-   6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-(3-[4-(methylthio)phenyl]pyrazin-2-yl}phenyl)quinoline,-   8-{3-[3-(4-fluorophenyl)pyrazin-2-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   8-(3-{2-(2-ethylpyridin-4-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,-   2-(4-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl    )phenyl)propan-2-ol,-   and pharmaceutically acceptable salts thereof.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl,adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyland the like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected to the oxy connecting atom.

The term “alkoxy” unless specifically stated otherwise includes an alkylgroup connected to the oxy connecting atom.

The term “aryl” unless specifically stated otherwise includes multiplefused ring systems as well as single ring systems such as, for example,phenyl or naphthyl. In the case of single rings “aryl” shall includeonly aromatic carbocycles. In the case of multiple rings fused together,“aryl” shall include carbocycles where at least one of the rings is anaromatic carbocycle such as in indanyl, 1,2,3,4-tetrahydronaphthaleneand 6,7,8,9-tertrhydro-5H-benzo[a]annulenenyl.

The term “aryloxy” unless specifically stated otherwise includesmultiple fused ring systems as mentioned above as well as single ringsystems such as, for example, phenyl or naphthyl, connected through theoxy connecting atom to the connecting site.

The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminus moiety. An alkyl with no carbonatoms is a direct bond when the alkyl is a bridging moiety.

The term “heterocyclo” unless specifically stated otherwise includes oneor more O, S, or N atoms. For example, heterocycles include ring systemsthat contain one or more O, S, or N atoms in the ring, includingmixtures of such atoms. The heteroatoms replace ring carbon atoms. Thus,for example, a heterocyclo of 5 ring members is a five membered ringcontaining from zero to 4 carbon atoms. Moreover, for purposes of thisspecification, heterocycles includes rings substituted with “oxo”, suchas pyridin-2-one.

Examples of heterocycles include, for example, pyridinyl,pyridin-one-yl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The term “heterocyclooxy” unless specifically stated otherwise describesa heterocyclo group connected through an oxy connecting atom to theconnecting site.

Examples of heterocyclo(C₁₋₆)alkyl include, for example, furylmethyl,furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

Other examples of heterocycloC₃₋₇alkyl include, for example, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, andthiomorpholinyl.

The term “N-heterocycloC₄₋₇alkyl” describes nonaryl heterocycliccompounds having 3-6 carbon atoms and one nitrogen atom forming thering. Examples include azetidinyl, pyrrolidinyl, piperidinyl, andperhydroazepinyl.

Examples of aryl(C₁₋₆)alkyl include, for example, phenyl(C₁₋₆)alkyl, andnaphthyl(C₁₋₆)alkyl.

Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₆)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁-C₄alkyl, and —OC(O)NHC₁-C₄alkyl.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

The term “oxide” of heteroaryl groups is used in the ordinary well-knownchemical sense and include, for example, N-oxides of nitrogenheteroatoms.

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be mixtures of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are benzenesulfonic, citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) Leukotrienereceptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii)corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptoragonists, vi) COX-2 selective inhibitors, vii) statins, viii)non-steroidal anti-inflammatory drugs (“NSAID”), and ix) M2/M3antagonists. The compositions include compositions suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular,and intravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions may be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of conditions such as asthma,chronic bronchitis, chronic obstructive pulmonary disease (COPD),eosinophilic granuloma, psoriasis and other benign or malignantproliferative skin diseases, endotoxic shock (and associated conditionssuch as laminitis and colic in horses), septic shock, ulcerativecolitis, Crohn's disease, reperfusion injury of the myocardium andbrain, inflammatory arthritis, chronic glomerulonephritis, atopicdermatitis, urticaria, adult respiratory distress syndrome, chronicobstructive pulmonary disease in animals, diabetes insipidus, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, arterialrestenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation,pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplantrejection and graft versus host disease, hypersecretion of gastric acid,bacterial, fungal or viral induced sepsis or septic shock, inflammationand cytokine-mediated chronic tissue degeneration, osteoarthritis,cancer, cachexia, muscle wasting, depression, memory impairment, tumourgrowth and cancerous invasion of normal tissues which are responsive toPDE4 inhibition, or alternatively about 0.5 mg to about 7 g per patientper day. For example, inflammation may be effectively treated by theadministration of from about 0.01 mg to 50 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about3.5 g per patient per day. Further, it is understood that the PDE4inhibiting compounds of this invention can be administered atprophylactically effective dosage levels to prevent the above-recitedconditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula L orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients-such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as PDE4 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), eosinophilic granuloma, psoriasis and otherbenign or malignant proliferative skin diseases, endotoxic shock (andassociated conditions such as laminitis and colic in horses), septicshock, celiac sprue, ulcerative colitis, Crohn's disease, reperfusioninjury of the myocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, chronic obstructive pulmonary disease in animals,diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernalconjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis,neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease,hypersecretion of gastric acid, bacterial, fungal or viral inducedsepsis or septic shock, inflammation and cytokine-mediated chronictissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting,depression, memory impairment, tumour growth and cancerous invasion ofnormal tissues - maladies that are amenable to amelioration throughinhibition of the PDE4 isoenzyme and the resulting elevated cCAMPlevels—by the administration of an effective amount of the compounds ofthis invention.

In addition to being useful in the treatment of cognitive deficit (suchas memory impairment, mentioned elsewhere in this specification) due topsycological dysfunction, neurological deficit (such as stroke) orpsychiatric dysfunction, the compounds of the invention are useful forenhancing cognition in a healthy subject (enhancing memory, learning,retention, recall, awareness and judgement).

The term “mammals” includes humans, as well as other animals such as,for example, dogs, cats, horses, pigs, and cattle. Accordingly, it isunderstood that the treatment of mammals other than humans is thetreatment of clinical correlating afflictions to those above recitedexamples that are human afflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the PDE4 inhibiting compound of this invention canbe advantageously used in combination with i) Leukotriene receptorantagonists, ii) leukotriene biosynthesis inhibitors, iii)corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptoragonists, vi) COX-2 selective inhibitors, vii) statins, viii)non-steroidal anti-inflammatory drugs (“NSAID”), and ix) M2/M3antagonists.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise. Ac = acetyl Bn = benzyl CAMPcyclic adenosine-3′,5′-monophosphate DBU =1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL = diisobutylaluminum hydrideDMAP = 4-(dimethylamino)pyridine DMF = N,N-dimethylformamide Et₃N =triethylamine GST glutathione transferase HMDS hexamethyldisilazide LDA= lithium diisopropylamide m-CPBA = metachloroperbenzoic acid MMPP =monoperoxyphthalic acid MPPM = monoperoxyphthalic acid, magnesium salt6H₂O Ms = methanesulfonyl = mesyl = SO₂Me Ms0 = methanesulfonate =mesylate NSAID = non-steroidal anti-inflammatory drug o-Tol =ortho-tolyl OXONE ® = 2KHSO₅.KHSO₄.K₂SO₄ PCC = pyridinium chlorochromatePDC = pyridinium dichromate PDE phosphodiesterase Ph = phenyl Phe =benzenediyl PMB = para-methoxybenzyl Pye = pyridinediyl r.t. = roomtemperature Rac. = racemic SAM = aminosulfonyl or sulfonamide or SO₂NH₂SEM = 2-(trimethylsilyl)ethoxymethoxy SPA = scintillation proximityassay TBAF = tetra-n-butylammonium fluoride Th = 2- or 3-thienyl TFA =trifluoroacetic acid TFAA = trifluoroacetic acid anhydride THF =tetrahydrofuran Thi = thiophenediyl TLC = thin layer chromatographyTMS-CN = trimethylsilyl cyanide TMSI trimethylsilyl iodide Tz = 1H (or2H)-tetrazol-5-yl C₃H₅ = allyl

Alkyl Group Abbreviations Me = Methyl Et = Ethyl n-Pr = Normal propyli-Pr = Isopropyl n-Bu = Normal butyl i-Bu = Isobutyl s-Bu = Secondarybutyl t-Bu = Tertiary butyl c-Pr = Cyclopropyl c-Bu = Cyclobutyl c-Pen =Cyclopentyl c-Hex = Cyclohexyl

Assays Demonstrating Biological Activity LPS and FMLP-Induced TNF-α andLTB₄ Assays in Human Whole Blood

Whole blood provides a protein and cell-rich milieu appropriate for thestudy of biochemical efficacy of anti-inflammatory compounds such asPDE4-selective inhibitors. Normal non-stimulated human blood does notcontain detectable levels of TNF-α and LTB4. Upon stimulation with LPS,activated monocytes express and secrete TNF-α up to 8 hours and plasmalevels remain stable for 24 hours. Published studies have shown thatinhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibitionand/or enhanced adenylyl cyclase activity occurs at the transcriptionallevel. LTB4 synthesis is also sensitive to levels of intracellular cAMPand can be completely inhibited by PDE4-selective inhibitors. As thereis little LTB₄ produced during a 24 hour LPS stimulation of whole blood,an additional LPS stimulation followed by fMLP challenge of human wholeblood is necessary for LTB₄ synthesis by activated neutrophils. Thus, byusing the same blood sample, it is possible to evaluate the potency of acompound on two surrogate markers of PDE4 activity in the whole blood bythe following procedure.

Fresh blood was collected in heparinized tubes by venipuncture fromhealthy human volunteers (male and female). These subjects had noapparent inflammatory conditions and had not taken any NSAIDs for atleast 4 days prior to blood collection. 500 μL aliquots of blood werepre-incubated with either 2 μL of vehicle (1MSO) or 2 μL of testcompound at varying concentrations for 15 minutes at 37° C. This wasfollowed by the addition of either 10 μL vehicle (PBS) as blanks or 10μL LPS (1 g/mL final concentration, #L-2630 (Sigma Chemical Co., St.Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (inPBS)). After 24 hours of incubation at 37° C., another 10 μL of PBS(blank) or 10 μL of LPS (1 μg/mL final concentration) was added to bloodand incubated for 30 minutes at 37° C. The blood was then challengedwith either 10 μL of PBS (blank) or 10 μL of FMP (1 μM finalconcentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15minutes at 37° C. The blood samples were centrifuged at 1500×g for 10minutes at 4° C. to obtain plasma. A 50 μL aliquot of plasma was mixedwith 200 μL methanol for protein precipitation and centrifuged as above.The supernatant was assayed for LTB₄ using an enzyme immunoassay kit(#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to themanufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS)using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) accordingto manufacturer's procedure. The IC₅₀ values of selected examples:Example: IC50 (μM) 115 0.61 167 0.139 1 0.155 19 0.046 24 0.054 41 0.04469 0.025 78 0.12 82 0.156 88 0.144 94 1.04 100 0.220 157 0.136

Anti-Allergic Activity in vivo

Compounds of the invention have been tested for effects on anIgE-mediated allergic pulmonary inflammation induced by inhalation ofantigen by sensitized guinea pigs. Guinea pigs were initially sensitizedto ovalbumin under mild cyclophosphamide-induced immunosuppression, byintraperitoneal injection of antigen in combinations with aluminumhydroxide and pertussis vaccine. Booster doses of antigen were given twoand four weeks later. At six weeks, animals were challenged withaerosolized ovalbumin while under cover of an intraperitoneallyadministered anti-histamine agent (mepyramine). After a further 48 h,bronchial alveolar lavages (BAL) were performed and the numbers ofeosinophils and other leukocytes in the BAL fluids were counted. Thelungs were also removed for histological examination for inflammatorydamage. Administration of compounds of the Examples (0.001-10 mg/kg i.p.or p.o.), up to three times during the 48 h following antigen challenge,lead to a significant reduction in the eosinophilia and the accumulationof other inflammatory leukocytes. There was also less inflammatorydamage in the lungs of animals treated with compounds of the Examples.

Spa Based PDE Activity Assay Protocol

Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IVcAMP-specific phosphodiesterases were screened in a 96-well plate formatas follows:

In a 96 well-plate at 30° C. was added the test compound (dissolved in 2μL DMSO), 188 mL of substrate buffer containing [2,8-3H] adenosine3′,5′-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 mM MgCl₂, 1 mM EDTA,50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 mLof human recombinant PDE4 (the amount was controlled so that ˜10%product was formed in 10 min.). The reaction was stopped after 10 min.by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech,Inc., Piscataway, N.J.). The product AMP generated was quantified on aWallac Microbeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg,Md.). The signal in the absence of enzyme was defined as the background.100% activity was defined as the signal detected in the presence ofenzyme and DMSO with the background subtracted. Percentage of inhibitionwas calculated accordingly. IC₅₀ value was approximated with anon-linear regression fit using the standard 4-parameter/multiplebinding sites equation from a ten point titration.

The IC₅₀ values of Examples in table below were determined with 100 nMcAMP using the purified GST fusion protein of the human recombinantphosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9expression system. The IC₅₀ values of selected examples: Example: IC50(nM) 115 2.2 167 0.4 1 0.3 19 1.0 24 0.4 41 1.0 69 0.6 78 0.4 82 3.1 881.6 94 4.3 100 4.1 157 1.7

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. Yields are givenfor illustration only. When given, NMR data is in the form of delta (δ)values for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMSA) as internal standard, determined at300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventionalabbreviations used for signal shape are: s. singlet; d. doublet; t.triplet; m. multiplet; br. broad; etc. In addition, “Ar” signifies anaromatic signal. Chemical symbols have their usual meanings; thefollowing abbreviations have also been used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. The substituents are the same as in Formula I exceptwhere defined otherwise.

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing general methods. Reactions are typically run under nitrogenatmosphere at ambient temperature if not otherwise mention. Anhydroussolvent such as TBF, DMF, Et₂O, DME and Toluene are commercial grade.Reagents are commercial grade and were used without any purification.Flash chromatography is run on silica gel (230-400 mesh).

All 8-aryl-quinoline of the type I can be prepared (Scheme 1 and 2)using a Suzuki type coupling to build the biaryl moieties. In a typicalSuzuki coupling reaction, all reagents except for the palladium catalystare mixed in the appropriate solvent. The mixture is then degassed byrefluxing for 15 min under nitrogen atmosphere then cooling to ambienttemperature or by applying two to three vacuum/nitrogen sequence. Thepalladium catalyst is then added and the reaction mixture is stirred atthe appropriate temperature until completion as monitored by TLC.

The substituents are the same as in Formula I except where definedotherwise. Compounds of the type I (Scheme 1) can be prepared in a twostep one-pot manner by generating in-situ the boronate analog of 8-bromoquinoline I followed by a palladium catalyzed coupling with theappropriate biaryl III

In most cases, compounds were prepared by the two procedures describedin Scheme 2. A Suzuki type coupling between the 8-bromoquinoline II andthe bromo-phenyl-boronic acid IV produced to the common intermediate V.The latter can be coupled with either an aryl-stannane of type VI or aboronic acid of type VII to generate the desired compound I.Alternatively, the arylbromide V can be converted to the correspondingpinacole boronate VIII by a PdCl₂(dppf)₂ catalyzed coupling reactionwith pinacole diborane. Subsequently, a Suzuki coupling of the boronateVIII with the appropriate heteroaryl halide or O-triflate IX willgenerate the desired compound I.

Boronic acid of the type XII can be prepared (Scheme 3) bylithium-halogen exchange at low temperature in THF or Et₂O on thecorresponding heteroaryl bromide X followed by the addition of atrialkyl-boronate (B(OR)₃). Hydrolysis, under acidic condition, of theresulting heteroaryl-boronate will generate the desired boronic acid XII(R═H). Likewise, lithium-halogen exchange or deprotonation at lowtemperature in THF or Et₂O followed by the addition of atrialkylstannyl-chloride (R₃SnCl) generates the stannane of type XI.These can be used as precursors for biaryl of type IX.

The heterocyclic Art groups can be constructed from the common aldehydeXIV or Q-CHO (scheme 4) prepared by Suzuki type coupling. The aldehydeXIV can lead to ethanone XV or ethanone XVI (scheme 5) by using amethodology described by M. Journet et al. in Tetrahedron Lett. 39, 1717(1998). They can serve as precursor for pyridinone XVII and XVII usingammonia and methyl propiolate as described for example in J.Heterocyclic Chem. 30, 1129 (1993). The ethanone XV or ethanone XVI canalso be lead to alpha bromo analogs XIX and XX which are used for theformation of thiazole, oxazole XXI, XXII and other heterocycle likequinoxaline XXIII, imidazothiazole XXIV or imidazopyridinyl XXV.

8-Bromoquinoline II with various substituent at position 6 can beprepared by the Skraup synthesis (Org. React. 7, 59-98,1953) using anappropiate aniline, an oxidizing agent such as 3-nitrophenylsulfonicacid and glycerol in strong acidic media such as sulfuric acid ormethanesulfonic acid (Scheme 6).

The common quinoline intermediates were prepared using the followingprocedures.

8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Preparation of 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline isdescribed in Patent Publication U.S. Pat. No. 6,410,563 B1 (2002).

3-{3-[1-methyl-1-(methylsulfonyl)ethyl]-1-naphthyl}benzaldehyde

Preparation of3-{3-[1-methyl-1-(methylsulfonyl)ethyl]-1-naphthyl}benzaldehyde isdescribed in Patent Publication U.S. Pat. No. 6,410,563 B1 (2002).

8-(3-Bromo-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A mixture of Quinoline 2 (1.0 eq), 3-bromophenylboronic acid (1.05 eq),Na₂CO₃ (2 M in H₂O; 3.6 eq) and Pd(PPh₃)₄ (0.03 eq) in DME (0.2 M) wasstirred at 80° C. for 8 h. The resulting mixture was cooled to roomtemperature and diluted with water under vigourous stirring. Theresulting precipitate was filtered and dried. Flash chromatography(Hex:EtOAc; 2:3) and stirring in a mixture of Et₂O and CH₂Cl₂ (10:1)yielded the title compound as a light yellow solid after filtration.

6-(1-Methanesulfonyl-1-methyl-ethyl)-8-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-quinoline

A mixture of Quinoline_(—)3 (1.0 eq), pinacole diborane ester(1.4 eq)and KOAc (3.5 eq) and PdCl₂(dppf)₂ (0.03 eq) in DMF (0.14 M) was stirredat 60° C. for 24 h. An extra amount of pinacole diborane (0.3 eq), KOAc(1.05 eq) and PdCl₂(dppf)₂ (0.01 eq) were added and the mixture wasstirred at 60° C. for 24 h. The resulting mixture was cooled to roomtemperature, diluted with EtOAc:Et₂O (1:1). The organic phase was washedwith water (3×), brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (CH₂Cl₂:EtOAc; 9:1) and stirring in Et₂O:EtOAc(10:1) afforded the title compound as a white solid. Subsequent flashchromatography (CH₂Cl₂:EtOAc; 9:1) on the mother liquor and stirring inEt₂O:EtOAc (10:1) afforded a second crop of the title compoundcontaining 5% of starting material.

8-bromo-N-cyclopropylquinoline-6-carboxamide Step 1:8-bromoquinoline-6-carboxylic acid

4-Amino-3-bromo-benzoic acid (1 eq) and glycerol (2.4 eq) was added tosulfuric acid (6.4M, reaction conc. 0.6M) at 0° C. After 15 min, thebath was removed and 3-nitro-phenylsulfonic acid sodium salt (1.3 eq)was added portionwise. The reaction mixture was heated gradually untilexothermic reaction started (between 110-140° C.), the internaltemperature was maintained below 170° C. for 1 h. The reaction mixturewas cooled to 50° C. and poured slowly into NH₄OH-ice (2:1). The titleproduct isolated by filtration, dissolved in warm 5% NH₄OH/MeOH anddiluted with CH₂Cl₂. This solution was filtered through silica geleluting with (NHOH, MeOH, CH₂Cl₂, 3:30:70). The residue was stirred inEtOH and the title product isolated by filtration.

Step 2: 8-bromo-N-cyclopropylquinoline-6-carboxamide

A solution of HATU (1.2 eq), 8-bromoquinoline-6-carboxylic acid (1 eq),diisopropylethylamine (2.5 eq) and cyclopropylamine (1.1 eq) was stirredat rt for 1h in DMF (0.2M). The reaction mixture was diluted with water,stirred for 2 h and extracted with EtOAc. The organic extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was crystallized in EtOAc and title product isolated byfiltration as a white powder.

2-(8-bromoquinolin-6yl)-2-methylpropanenitrule

Preparation of 2-(8-bromoquinolin-6-yl)-2-methylpropanenitrile isdescribed in Patent Publication U.S. Pat. No. 6,410,563 B1 (2002).

General Method of Synthesis:

Coupling-1; General Procedure for Aryl-Aryl Coupling

A mixture of boronic acid or boronate ester (1.0 eq), aryl bromide(chloride or iodide) (1.1-2.0 eq.), Na₂CO₃ (3.0-3.5 eq.; 2 M in H₂O) andPdCl₂(dppf)₂ or Pd(OAc)₂—(Ph₃P)₂ or Pd(Ph₃P)₄ orPd(1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride)₂ (0.05 eq.) inDME (or n-Propanol or Dioxane or DMF) (0.05-0.2 M) was stirred at 60-80°C. for 1-18 h. The mixture was cooled to room temperature andconcentrated. Flash chromatography afforded the title compound.(Coupling using Aryl Iodide generally proceeds at lower temperature20-60 ° C.).

Coupling-2; General Procedure for Aryl-Aryl Coupling

A mixture of boronic acid or boronate ester (1.0 eq), aryl bromide (orchloride or iodide) (1.1-2.0 eq), CsF (2.5 eq) or aqueous Na₂CO₃ (2M),Pd₂(dba)₃ (1.5%) and (t-Bu)₃P (4.5%) in THP or dioxane (0.05-0.2 M) wasstirred at 20° C. for 12-18 h. The mixture was concentrated, dilutedwith EtOAc and water then extracted. Flash chromatography afforded thetitle compound.

Coupling-3; General Procedure for Aryl-Aryl Coupling

A mixture of Aryltributyltin (1-2 eq), aryl bromide (1-2 eq), CuI (0.05eq), PdCl₂(dppf) (0.05 eq) in dioxane (0.05-0.2 M) was stirred at 100°C. for 12-18 h. The mixture was concentrated, diluted with EtOAc andwater then extracted. Flash chromatography afforded the title compound.

Oxid-1; General Procedure for Oxidation of Sulfide to Sulfone

To a solution Sulfide (1.0 eq.) in TBF:MeOH:H₂O (2:2:1) (oralternatively replacing water with saturated aqueous NaHCO₃), was addedOxone (2.2 eq.). The mixture was stirred for 12 h at room temperature,poured in water and extracted with EtOAc (2×). The combined organicextracts were washed with aqueous NaHCO₃, brine, dried over MgSO₄ orNa₂SO₄, filtered and concentrated. Flash chromatography afforded thetitle compound.

Oxid-2: General Procedure for Oxidation of Pyridinyl toPyridinyl-N-Oxide:

To a solution of Pyxidinyl (1.0 eq.) in CH₂Cl₂ (0.1 M) was added m-CPBA(1.3 eq.). The mixture was stirred at room temperature for 12 h,quenched with Ca(OH)₂ (0.7 eq) diluted with CH₂Cl₂ and filtered. Thefiltrate was concentrated and flash chromatography afforded the titlecompound.

Alternatively, the reaction mixture was quenched with EtOAc and aqueousNaHCO₃, the combined organic extracts were washed with aqueous NaHCO₃,brine, dried over MgSO₄ or Na₂SO₄, filtered and concentrated. Flashchromatography afforded the title compound.

Cer-1; General Procedure for Grignard Type Addition on Ester and KetoneUsing CeCl₃

A heterogeneous solution of CeCl₃ (1.5 eq) and ester (1 eq) in TPF(0.1M) is sonicated at room temperature for 15 minutes. The resultingsuspension is cooled to −78° C. and RMgX (Cl, Br, I, 6 eq) is added. Themixture is let to warm to −25° C. over a 2 hours period. The reaction isquenched with saturated solution of NH₄Cl and diluted with ethylacetate. The organic phase is extracted, washed with brine and dry overMgSO₄ and concentrated. The residu was purified by flash chromatography(Hexane:EtOAc) or precipitated with ether/ethyl acetate to afforded thetitle compound.

Alternatively ketones can be used as starting material with 3 eq ofGrignard reagent (RMgX).

Thio-1: General Procedure for Conversion of Nitrile to Thioaride:

Heating nitrile derivative in MeOH at reflux with ammonium sulfide asdescribed in SPYCHALA, J.; Synth Commun. 1997, 27 (19), 3431-3440. Theproduct is generally purified by filtration, wash with water and airdried.

Bi-Aryl intermediates were prepared using the following procedures.

Step 1: 3-bromo-5-[4-(methylthio)phenyl]pyridine

Prepared according to the procedure Coupling-2 using[4-(methylthio)phenyl]boronic acid and 3,5-dibromopyridine asstarting-material. Flash chromatography (Hex:EtOAc; 95:5-85:15) affordedthe title compound

Step 2: 3-bromo-5-[4-(methylsulfonyl)phenyl]pyridine 1-oxide

Prepared according to the procedure Oxid-1 and using oxone in excess (5eq). The residue was stirred vigorously in EtOAc then isolated byfiltration.

Step 1: 3-bromo-5-[3-(methylthio)phenyl]pyridine

Prepared according to the procedure Coupling-2 using[3-(methylthio)phenyl]boronic acid and 3,5-dibromopyridine as startingmaterial. Flash chromatography (Hex:EtOAc; 95:5-85:15) afforded thetitle compound.

Step 2: 3-bromo-5-[3-(methylsulfonyl)phenyl]pyridine 1-oxide

Prepared according to the procedure Oxid-2 and using mCPBA (3.2 eq). Theresidu was stirred vigorously in Et₂O then isolated by filtration.

Prepared according to the procedure described for Pyr_(—)2 using[2-(methylthio)phenyl]boronic acid as starting material. The residue wasstirred vigorously in Et₂O then isolated by filtration.

Step 1: 3-amino-2-[4-(methylthio)phenyl]pyridine

Prepared according to the procedure Coupling-1 using[4-(methylthio)phenyl]boronic acid and 2-amino-1-chloropyridine asstarting material. Flash chromatography (Hex:EtOAc; 60:40-50:50)afforded the title compound.

Step 2: 3-amino-2-[4-(methylsulfonyl)phenyl]pyridine

Prepared according to the procedure Oxid-1. Flash chromatography(Hex:EtOAc; 50:50-20:80) afforded the title compound as a white solid.

Step 3: 3-Iodo-2-[4-(methylsulfonyl)phenyl]pyridine

To a solution of 3-amino-2-[4-(methylsulfonyl)phenyl]pyridine (1.0 eq.)in AcOH:CH₂Cl₂ (1:1, 0.13 M) at −20° C. was added I₂ (1.5 eq), KI (1.5eq) then NaNO₂(1.5 eq). The mixture was stirred at 20° C. for 2 h thendiluted with EtOAc and water. The organic extracts were washed withaqueous NaHCO₃, brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (Hex:EtOAc; 40:60) afforded the title compound as awhite solid.

Prepared according to the procedure described for Pyr_(—)2 usingphenylboronic acid as starting material. Flash chromatography(Hex:EtOAc; 30:70), stirring vigorously in EtOAc-Et₂O-hexane thenisolated by filtration.

Prepared according to the procedure described for Pyr_(—)2 using3,5-dichloro-phenylboronic acid as starting material. Flashchromatography (Hex:EtOAc; 30:70), stirring vigorously in EtOAc-Et₂Othen isolated by filtration.

Prepared according to the procedure described for Pyr_(—)2 using3,4-dimethoxy-phenylboronic acid as starting material. Flashchromatography (Hex:EtOAc; 40:70 and then using toluene:acetone, 95:5)afforded the title compound.

Step 1: 5-bromo-N′-hydroxypyridine-3-carboximidamide

A mixture of 3-bromo-5-cyanopyridine (1.0 eq), hydroxylaminehydrochloride (1.5 eq.), K₂CO₃ (2.1 eq) in ethanol (0.1 M) was stirredat 80° C. for 3 days. The mixture was concentrated, diluted with EtOAcand aqueous NaHCO₃. The title compound was isolated by filtration asbeige solid.

Step 2: 3-bromo-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine

To a solution of 5-bromo-N′-hydroxypyridine-3-carboximidamide (1.0 eq.)in pyridine was added acetyl chloride (2 eq). The reaction stirred at100° C. for 1 h and 2 eq of acetyl chloride was added. After 1 h, themixture was cooled, diluted with EtOAc and aqueous NaHCO₃. The organicextracts were washed with aqueous NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography (Hex:EtOAc; 70:30)afforded the title compound as a white solid.

Step 3: 3-bromo-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine 1-oxide

Prepared according to the procedure Oxid-2. Flash chromatography (EtOAc)afforded the title compound as a white solid.

Step 1: 3-bromo-5-(1H-tetraazol-5-yl)pyridine

To a mixture of 3-bromo-5-cyanopyridine (1.0 eq.) and triethylamine (1.3eq in toluene (0.7 M) was added AcOH (1.3 eq). The reaction was stirredat 100° C. for 12 h, cooled, diluted with EtOAc and 1% AcOH solution.The organic extracts were washed with brine, dried over Na₂SO₄, filteredand concentrated to afford the title compound as a brown solid.

Step 2: 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine

A solution of 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine inacetic anhydride (0.8M) was at 140° C. for 2. The mixture wasconcentrated, diluted with EtOAc and aqueous NaHCO₃. The organicextracts were washed with aqueous NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. Flash chromatography Oex:EtOAc; 70:30)afforded the title compound as a white solid.

Step 3: 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine 1-oxide

Prepared according to the procedure Oxid-2. Flash chromatography(EtOAc:MeOH, 100:0-95:5) afforded the title compound.

Step 1: 2-chloro-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine

A mixture of 2-chloro nicotinoyl chloride (1.0 eq.) and N′-hydroxyethanimidamide (1.1 eq) in pyridine (0.6 M) was stirred at 100° C. for47 h and then concentrated. The residue was purified by flashchromatography (Hexane:EtOAc, 70:30) to afforded the title compound.

Step 2: 2-(benzyloxy)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine

To a solution of benzyl alcohol (1.5 eq) in DMF (0.4M) was added NaH(1.5 eq, 60%) followed by2-chloro-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine (1 eq) in DMF (0.5M)after 30 min.). The reaction was stirred at 20° C. for 1 h, diluted withEt₂O and water. The organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc;80:20) afforded the title compound.

Step 3: 3-(3-methyl-1,2,4oxadiazol-5-yl)pyridin-2-ol

A solution of 2-(benzyloxy)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine inCH₂Cl₂-TFA (0.25M) was stirred 15 min at 20° C. and then concentrated.The residu was diluted with EtOAc and aqueous NaHCO₃ The organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated to afforded the title compound.

Step 4: 5-bromo-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol

A solution 3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol in AcOH (0.2M)and bromine (1.2 eq) was stirred 18 h at 20° C. and then concentrated.The residue was co-evaporated with benzene (2X) and used as such in thenext step.

Step 5: 2-(benzyloxy)-5-bromo-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine

A solution 5-bromo-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol (1 eq)in benzene (0.05M) was added silver carbonate (1 eq) and benzyl bromide(1.2 eq). The reaction mixture was stirred 6 h at 20° C. and thenconcentrated. The residue was purified by flash chromatography(Hexane:EtOAc, 90:10) to afforded the title compound.

Step 1: 3-bromo-5-(3-methyl-1,2,4oxadiazol-5-yl)pyridine

A mixture of 5-bromo nicotinic acid(1.0 eq.) and CDI (1.1 eq) in DMF(0.25M) was stirred at 20° C. for 5 min and then N′-hydroxyethanimidamide (1.1 eq) in pyridine (0.6 M) was added. The reactionmixture was stirred at 110° C. for 15 h, cooled to rt and poured intowater. The title compound was isolated by filtration as a solid.

Step 2: 3-bromo-5-(3-methyl-1,2,4oxadiazol-5-yl)pyridine 1-oxide

Prepared according to the procedure Ox-2. The residu was stirredvigorously in EtOAc then isolated by filtration.

Step 1: 5-bromo-2-[4-(methylthio)phenyl]pyridine

Prepared according to the procedure Coupling-2 using[4-(methylthio)phenyl]boronic acid and 2,5-dibromo pyridine afforded thetitle compound in a mixture of isomer containing2-bromo-5-[4-(methylthio)phenyl]pyridine.

Step 2: 5-bromo-2-[4-(methylsulfonyl)phenyl]pyridine

Prepared by submitting the mixture of isomer to the procedure Oxid-1.Flash chromatography (DCM:EtOAc 95:5-50:50) afforded the title compound(less polar isomer).

Step 3: 5-bromo-2-[4-(methylsulfonyl)phenyl)pyridine 1-oxide

Prepared according to the procedure Oxid-2. Flash chromatography(DCM:EtOAc 75:25-0:100) afforded the title compound.

Prepared according to the procedure as described for Pyr_(—)12 using themore polar isomer isolated from step 2.

Prepared according to the procedure as described in Bioorg. Med. Chem.Lett., 1999, 9, 1715, U.S. Pat. No. 5,861,419, 1999.

Step 1: 1-(4-chlorophenyl)pyridin-2(1H)-one

Prepared according to the procedure as described in Chem.Pharm.Bull.,1997, 45, 719. Flash chromatography (Hex:EtOAc; 70:30) afforded thetitle compound.

Step 2: 3-bromo-1-(4-chlorophenyl)pyridin-2(1H)-one

A solution 1-(4-chlorophenyl)pyridin-2(1H)-one (1 eq) andtetrabutylammonium tribromide (1.2 eq) in chloroform (0.1M) was stirred6 h at reflux. The reaction mixture was diluted with aqueous NaHCO₃solution and aqueous Na₂S₂O₃ solution. The organic extracts were washedwith brine, dried over MgSO₄, filtered and concentrated. The residu waspurified by flash chromatography (Hexane:EtOAc, 80:20) to afforded thetitle compound.

Step 1: 3-bromo-5-(2H-tetraazol-5-yl)pyridine

A solution of 3-bromo-5-cyanopyridine (1 eq), sodium azide (1.2 eq),triethylamine (1.2 eq) and AcOH (1.2 eq) was stirred at 100C for 14 h.The reaction mixture was cooled to rt, diluted with aqueous acetic acidsolution and extracted with EtOAc. The organic extracts were washed withbrine, dried over MgSO₄, filtered and concentrated to afford the titlecompound.

Step 2: 3-bromo-5-(2-methyl-2H-tetraazol-5-yl)pyridine

To a solution of tetrazole from step 1 in CH₂Cl₂-MeOH (5:1, 0.1M) wasadded CH₂N₂ (in ether) until reaction completed by TLC. The reactionmixture was concentrated to afford the title compound.

Step 3: 3-bromo-5-(2-methyl-2H-tetraazol-5-yl)pyridine 1-oxide

Prepared according to the procedure Oxid-2. Flash chromatography(CH₂Cl₂—MeOH, 98:2) afforded the title compound.

Step 1: 3-[4-(methylthio)phenyl]thiophene

Prepared according to the procedure Coupling-1 using[4-(methylthio)phenyl]boronic acid and 3-bromothiophene as startingmaterial. Flash chromatography (CH₂Cl₂) afforded the title compound.

Step 2: 2-bromo-3-[4-(methylthio)phenyl]thiophene

To a solution of thiophene from step 1 (1.0 eq) in CH₂Cl₂/AcOH (1:1,0.1M) was added NBS (1.05 eq). The mixture was stirred 1.5 h at r.t.,diluted with EtOAc and aqueous NaHCO₃. The organic extracts were washedwith water, brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (Hexane:EtOAc, 80:20) afforded the title compound.

Step 3:5-bromo-N-isopropyl-4-[4-(methylthio)phenyl]thiophene-2-carboxamide

To a solution of diisopropylamine (1.05 eq) in TBF at −78° C. was addedBuLi (1.6M, Hexane, 1.05 eq) dropwise. The mixture was stirred 10 min at0° C., cooled to −78° C. and thiophene from step 2 added. After 30 minat −50° C., isopropyl isocyanate was added. The mixture was stirred 1 hat rt, diluted with EtOAc and aqueous NaHCO₃. The organic extracts werewashed with water, brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (CH₂Cl₂).afforded the title compound.

Step 4:5-bromo-N-isopropyl-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide

Prepared according to the procedure Oxid-1. Flash chromatography(CH₂Cl₂: EtOAc, 90:10) afforded the title compound.

Prepared according to the general procedure Coupling-1 using4-methylthiobenzene boronic acid and 1-bromo-2-iodobenzene. Flashchromatography (Hexane:EtOAc, 100:0-95:5) afforded the title compound asan oil.

A mixture of 5-(2-bromophenyl)-2H-tetraazole (1.0 eq) in aceticanhydride (1M) was heated at 120° C. for 2 h and then concentrated.Flash chromatography (Hexane:EtOAc, 70:30) afforded the title compoundas a white solid.

Step 1: methyl 6-amino-4′-(methylthio)-1,1′-biphenyl-3-carboxylate

Prepared according to the general procedure Coupling-1 (CsF, DME, 20°C.) using [4-(methylthio)phenyl]boronic acid and methyl4amino-3-iodo-benzoate as starting material. Flash chromatography(Hexane:EtOAc, 70:30) afforded the title compound as a white solid.

Step 2: methyl 6-amino-4′-(methylsulfonyl)-1,1′-biphenyl-3-carboxylate

Prepared according to the general procedure Oxid-1. Flash chromatography(Hexane:EtOAc, 50:50) afforded the title compound.

Step 3: methyl 6-iodo-4′-(methylsulfonyl)-1,1′-biphenyl-3-carboxylate

To the amino from step 2 (1.0 eq) in CH₂Cl₂—AcOH (1:1) at −20° C. wasadded iodine (1.5 eq), KI (1.5 eq) followed by NaNO₂ (1.2 eq). Thereaction mixture was stirred at r.t. for 1 h, diluted with EtOAc, asolution of Na₂CO₃ and a solution Na₂S₂O₃. The organic extracts werewashed with water, brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (Hexane:EtOAc, 30:20-20:30) afforded the titlecompound as a pale yellow solid.

Step 1: 2-[5-(tributylstannyl)-1,3-thiazol-2-yl]propan-2-ol

To a solution of thiazole (1.0 eq) in TBF (0.2M) at −78° C. was addednBuLi (1.6M, 1.1 eq). After 1 h at −78° C., acetone (1.0 eq) was addedand the mixture stirred 30 min at −78° C., 5 min −50° C. then cooledback to −78° C. to add a second equivalent of nBuLi (1.6M, 1.1 eq).After 1.5 h at −78° C., tri-n-butyltin chloride (1.2 eq) was added andthe mixture stirred 12 h at −78° C. The reaction mixture was dilutedwith Et₂O and a solution of NH₄Cl. The organic extracts were washed withwater, brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (Hexane:EtOAc, 90:10) afforded the title compound.

Step 2: 2-[5-(2-bromophenyl)-1,3-thiazol-2-yl]propan-2-ol

A solution of stannane from step 1 (1.0 eq), 1-bromo-2-iodo-benzene (2.1eq), CuI (0.2 eq), PdCl₂(dppf) (0.1 eq) in DMF was heated 1 h at 80° C.The reaction mixture was diluted with EtOAc and a solution of NH4Cl. Theorganic extracts were washed with water, brine, dried over MgSO₄,filtered and concentrated. Flash chromatography (Hexane:EtOAc, 80:20)afforded the title compound.

Step 1: 4(3-bromophenyl)pyridine

Prepared according to the general procedure Coupling-1 using4-pyridinylboronic acid and 1,3-dibromobenzene. Flash chromatography(Hexane:EtOAc, 70:30) afforded the title compound.

Step 2: 4-(3-bromophenyl)pyridine 1-oxide

Prepared according to the general procedure Oxid-2. Flash chromatography(EtOAc:MeOH, 100:0 to 95:5) afforded the title compound.

EXAMPLE 18-(3-{2-(3-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Step 1: diphenyl anilino[4-(methylthio)phenyl]methylphosphonate

To a solution of 4-methylthiobenzaldehyde (1.0 eq) dissolved in hotacetonitrile was added aniline (1.2 eq) and diphenyl phosphite (1.6 eq).The reaction mixture was stirred at 20° C. for 18 h and thenconcentrated. The residue can be purified by flash chromatography ifnecessary.

Step 2:2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1-[4-(methylthio)phenyl]ethanone

To a solution of phosphonate from step 1 (1.2 eq) dissolved in DMF(0.2M) was added cesium carbonate (1.5 eq), Quinoline_(—)2 (1.0 eq) andisopropanol (20%, v/v). The reaction mixture was stirred at 70° C. for30 min (or 20° C. for 18 h), cooled to rt diluted with HCl (6N), stirredfor 2 h and extracted with EtOAc. The organic extracts were washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (Hexane:EtOAc, 50:50) to afforded thetitle compound.

Step 3:2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1-[4-(methylsulfonyl)phenyl]ethanone

Prepared according to the procedure Oxid-1. Flash chromatography(Hexane:EtOAc) afforded the title compound.

Step 4:2-bromo-2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl)quinolin-8-yl}phenyl)-1-[4-(methylsulfonyl)phenyl]ethanone

A solution of ketone from step 3 (1.0 eq) in chloroform (0.2M) withpolymer-supported tribromide (1 mmol/g, 1.2 eq) was heated at-reflux for1-2 h, filtered and concentrated to afforded the title compound.

Step 5:8-(3-{2-(3-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

To a solution of the alpha-bromoketone from step 4 (1.0 eq) in DMF(0.1M) was added 3-chlorobenzenecarbothioamide (1.0 eq). The mixture washeated at 40-120° C. for 1-3 h, cooled, diluted with water, saturatedNaHCO₃ solution and ether. The organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography (Hexane:EtOAc) to afforded the title compound.

¹H NMR (500 MHz, DMSO-d₆): δ 8.85 (dd, 1H), 8.46 (dd, 1H), 8.22 (d, 1H),8.04 (s, 1H, 7.95-7.90 (m, 6H), 7.73 (m, 2H), 7.55 (m, 4H), 7.48 (d,1H), 3.28 (s, 3H), 2.74 (s, 3H), 1.85 (s, 6H).

Following examples (Table 1) were prepared according to the proceduredescribed for EXAMPLE 1. Non-commercial thioamide used in step 5 ofexample 1, were prepared according to general procedure Thio-1. TABLE 1

ESI-LRMS Ex #: R group name (M + 1)⁺ 2 Amino 709.8 3 2-biphenyl 636.5 43-biphenyl 636.6 5 N-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-yl 729.76 N-(tert-butoxycarbonyl)azetidin-3-yl 639.6 7N-(tert-butoxycarbonyl)pyrrolidin-3-yl 653.9 8 3-chloro-4-fluorophenyl611.3 9 4-chlorophenoxymethyl 624.4 10 2-chlorophenyl 594.5 114-chlorophenyl 593.3 12 Ethoxycarbonyl 635.3 13 furan-2-yl 550.5 14furan-3-yl 550.4 15 imidazol-2-yl 550.4 16 indan-1-yl 600.6 17indan-2-yl 600.6 18 1H-indol-2-yl 599.5 19 1H-indol-3-yl 599.6 201H-indol-4-yl 599.4 21 1H-indol-5-yl 599.5 22 1H-indol-6-yl 599.6 231H-indol-7-yl 599.5 24 isoquinolin-1-yl 611.5 25 isoquinolin-4-yl 611.526 isoquinolin-5-yl 611.5 27 isoquinolin-8-yl 690.5 28 isoxazol-3-yl551.5 29 3-methoxycarbonylphenyl 697.2 30 4-methoxycarbonylphenyl 697.231 Methyl 577.3 32 1-methyl-1H-pyrazol-3-yl 564.5 331-methyl-1H-pyrazol-4-yl 564.6 34 1-methyl-1H-pyrazol-5-yl 564.5 352-methylphenyl 653.3 36 3-methylphenyl 653.3 37 4-methylphenyl 574.6 382-methylpyridin-5-yl 575.5 39 Methylsulfonylmethyl 576.5 402-methylsulfonylphenyl 717.3 41 3-methylsulfonylphenyl 717.3 424-methylsulfonylphenyl 717.3 43 morpholin-4-ylmethyl 575.5 44 Phenyl639.3 45 Pyrazinyl 562.4 46 1H-pyrazol-3-yl 550.4 47 pyridin-2-yl 561.548 pyridin-3-yl 561.5 49 pyridin-4-yl 561.5 50 3-pyridinylmethyl 575.651 pyrimidin-2-yl 562.4 52 pyrimidin-4-yl 562.4 53 pyrimidin-5-yl 562.454 quinolin-4-yl 611.5 55 quinolin-5-yl 611.5 56 quinolin-8-yl 611.5 575,6,7,8-tetrahydro-1,8-naphthyridin-2-yl 695.6 586,7,8,9-tetrahydro-5H-benzo[a][7]annulen-5-yl 628.6 596,7,8,9-tetrahydro-5H-benzo[a][7]annulen-6-yl 628.6 60tetrahydrofuran-2-yl 554.5 61 1,2,3,4-tetrahydronaphthalen-1-yl 615.7 621,2,3,4-tetrahydronaphthalen-2-yl 615.6 63 1,3-thiazol-2-yl 567.3 641,3-thiazol-5-yl 567.4 65 thiophen-2-yl 566.2 66 thiophen-3-yl 566.3

EXAMPLE 676-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-[4-(methylsulfonyl)phenyl]-2-(1-oxidopridin-4-yl)-1,3-thiazol-5-yl]phenyl}quinoline

Prepared according to the general procedure Oxid-2 using EXAMPLE 49 asstarting material.

¹H NMR (500 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.45 (dd, 1H), 8.28-8.26(m, 3H), 8.10 (d, 1H), 8.04 (d, 2H), 8.01 (d, 2H), 7.96 (d, 2H), 7.86(s, 1H), 7.83 (d, 1H), 7.61 (t, 1H), 7.58-7.55 (m, 2H), 3.14 (s, 3H),2.69 (s, 3H), 1.96 (s, 6H).

ESI-LRMS (M+1) 656.4

EXAMPLE 686-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-[4-(methylsulfonyl)phenyl]-2-(1-oxidopyridin-3-yl)-1,3-thiazol-5-yl]phenyl}quinoline

Prepared according to the general procedure Oxid-2 using EXAMPLE 48 asstarting material.

¹H NMR (500 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.79 (s, 1H), 8.44 (dd,1H), 8.28 (d, 1H), 8.25 (d, 1H), 8.10 (d, 1H), 8.03 (d, 2H), 7.97 (d,2H), 7.89-7.84 (m, 3H), 7.63 (t, 1H), 7.58-7.47. (m, 3H), 3.15 (s, 3H),2.70 (s, 3H), 1.96 (s, 6H).

ESI-LRMS (M+1) 656.3

EXAMPLE 692-(3-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}phenyl)propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide and EXAMPLE 29 as starting material.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.44 (dd, 1H), 8.28 (dd,2H), 8.09 (d, 1H), 8.01 (d, 2H), 7.95 (d, 2H), 7.92 (d, 1H), 7.86 (s,1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.60 (t, 1H), 7.57-7.54 (m, 2H), 7.48(t, 1H), 4.28 (s, 0.6H), 3.13 (s, 3H), 2.69 (s, 3H), 1.96 (s, 6H), 1.58(s, 6H).

ESI-LRMS (M+1) 617.4

EXAMPLE 703-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}benzoicacid

To a solution of EXAMPLE 29 in THF/MeOH/H₂O (0.05M) was added LiOH (2N,5 eq). The reaction mixture was stirred at rt for 2 h, acidified withAcOH, diluted with water and extracted with CH₂Cl₂. The organic extractswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The title compound was isolated by filtration from acetone/ether as asolid.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.72 (s, 1H), 8.44 (dd,1H), 8.31 (d, 1H), 8.27 (d, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 8.03 (d,2H), 7.96 (d, 2H), 7.88 (s, 1H), 7.83 (d, 1H), 7.69 (t, 1H), 7.61 (t,1H), 7.58-7.54 (m, 2H), 3.14 (s, 3H), 2.69 (s, 3H), 1.96 (s, 6H).

ESI-LRMS (M+1) 683.3

EXAMPLE 71 2-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide and EXAMPLE 12 as starting material.

¹H NMR (500 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.45 (dd, 1H), 8.27 (d,1H), 8.09 (d, 1H), 7.90 (m, 4H), 7.77 (m, 2H), 7.56 (m, 2H), 7.47 (m,1H), 5.26 (s, OH), 3.10 (s, 3H), 2.70 (s, 3H), 1.95 (s, 6H), 1.70 (s,6H).

EXAMPLE 726-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline

Step 1:5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazole-2-carboxylicacid

To a solution of EXAMPLE 12 in TBF/MeOH/H₂O (0.05M) was added LiOH (2N,2 eq). The reaction mixture was stirred at rt for 2h, acidified withHCO₂H, diluted with water and extracted with EtOAc. The organic extractswere washed with brine and concentrated to afford he title compound as asolid.

Step 2:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline

To a solution of acid from step 1 in DMF (0.05M) was added CDI (1.1 eq)and, after 5 min, acetamidoxime (1.1 eq). The reaction mixture wasstirred at rt for 1 h and 18 h at 110° C. The reaction mixture wascooled to rt and poured into water. The residue was purified by flashchromatography (toluene:EtOAc, 45:55) to afforded the title compound anddecarboxylated analog EXAMPLE 73 (more polar product).

¹H NMR (500 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.47 (dd, 1H), 8.30 (d,1H), 8.12 (d, 1H), 8.01 (s, 4H), 7.90 (m, 2H), 7.60 (m, 3H), 3.18 (s,3H), 2.70 (s, 3H), 2.52 (s, 3H), 1.95 (s, 6H).

EXAMPLE 736-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline

Prepared according to the procedure described for EXAMPLE 72.

¹H NMR (500 MHz, acetone-d₆): δ 9.15 (s, 1H), 8.88 (dd, 1H), 8.43 (dd,1H), 8.25 (d, 1H), 8.08 (d, 1H), 7.92 (m, 4H), 7.80 (m, 2H), 7.59 (t,1H), 7.55 (dd, 1H), 7.50 (m, 1H), 3.12 (s, 3H), 2.70 (s, 3H), 1.95 (s,6H).

EXAMPLE 74N-cyclopropyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazole-2-carboxamide

To a solution of EXAMPLE 12 in CH₂Cl₂ (0.05M) was added cyclopropylamine(4 eq) and trimethylaluminum (2M, Hexanes, 4 eq). The reaction mixturewas stirred at rt for 18 h. The reaction mixture was diluted slowly witha saturated NH₄Cl solution, a 1M sodium potassium tartrate solution andEtOAc. The mixture was extracted with EtOAc, the organic extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash chromatography (EtOAc) to afford the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.86 (dd, 1H), 8.43 (dd, 1H), 8.31 (d,1H), 8.26 (d, 1H), 8.07 (d, 1H), 7.91 (s, 4H), 7.83 (m, 2H), 7.55 (m,3H), 3.12 (s, 3H), 2.95 (m, 1H), 2.69 (s, 3H), 1.95 (s, 6H), 0.78 (m,2H), 0.73 (m, 2H).

EXAMPLE 756-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(6-methyl-1-oxidopyridin-3-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline

Prepared according to the general procedure Oxid-2using EXAMPLE 38 asstarting material.

¹H NMR (500 MHz, acetone-d₆): δ 8.87 (m, 2H), 8.44 (dd, 1H), 8.26 (d,1H), 8.09 (d, 1H), 8.0-7.9 (m, 2H), 8.0-7.9 (m, 5H), 7.67-7.5 (m, 4H),3.13 (s, 3H), 2.7 (s, 3H), 2.45 (s, 3H), 1.95 (s, 6H).

EXAMPLE 762-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1.3-thiazol-2-yl]propan-2-ol

Step 1: ethyl4-(4chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazole-2-carboxylate

Prepared according to the procedure described for EXAMPLE 1 using4-chloro benzaldehyde in step 1 and ethyl thiooxamate in step 5. Flashchromatography (Hexane:EtOAc, 50:50-20:80) afforded the title compound.

Step 2:2-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide. Flash chromatography (Hexane:EtOAc, 35:65) afforded the titlecompound as a white foam.

¹H NMR (500 MHz, acetone-d₆): δ 8.85 (dd, 1H), 8.40 (dd, 1H), 8.25 (d,1H), 8.05 (s, 1H), 7.75 (m, 2H), 7.65 (d, 3H), 7.35 (d, 2H), 7.0 (m,2H), 5.10 (s, OH), 2.66 (s, 3H), 1.95 (s, 6H), 1.7 (s, 6H).

EXAMPLE 776-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-methyl-4[-4(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}phenyl)quinoline

Prepared according to the procedure described for EXAMPLE 1 usingacetamide at 120° C. in step 5. Flash chromatography (CH₂Cl₂: EtOAc,80:20) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.45 (dd, 1H), 8.27 (d,1H), 8.12 (d, 1H), 8.03 (d, 2H), 7.98 (m, 3H), 7.80 (d, 1H), 7.70 (m,1H), 7.62 (m, 1H), 7.57 (m, 1H), 3.12 (s, 3H), 2.7 (s, 3H), 2.52 (s,3H), 1.95 (s, 6H).

EXAMPLE 782-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol

Step 1: ethyl4-(3-{6-1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazole-2-carboxylate

Prepared according to the procedure described for EXAMPLE 1 usingQuinoline_(—)2 in step 1,4-methylthiobenzaldehyde in step 2 and ethylthiooxamate in step 5.

Step 2:2-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazol-2-yl}propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide. Flash chromatography (CH₂Cl₂:MeOH, 98:2) afforded the titlecompound.

Step 3:2-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol.

Prepared according to the general procedure Oxid-1. Flash chromatography(toluene:acetone, 70:30) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.26 (d,1H), 8.05 (d, 1H), 7.96 (d, 2H), 7.87 (t, 1H), 7.73 (d, 2H), 7.72 (d,1H), 7.63 (d, 1H), 7.55 (dd, 1H), 7.50 (t, 1H), 5.20 (s, OH), 3.13 (s,3H), 2.71 (s, 3H), 1.97 (s, 6H), 1.71 (s, 6H).

EXAMPLE 791,1,1-trifluoro-N-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}methanesulfonamide

To a suspension of EXAMPLE 2 in CH₂Cl₂ at −78° C. was addedtriethylamine (4 eq) and Tf₂O (2.2 eq). The reaction was stirred at −78°C. 15 min then warmed to 20° C. for 1 h, diluted with NaHCO₃ solutionand CH₂Cl₂ and stirred 15 min. The organic extracts were washed withbrine, dried over Na₂SO₄, filtered and concentrated. Flashchromatography (EtOAc) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.27 (d,1H), 8.06 (d, 1H), 7.89 (d, 2H), 7.87 (d, 2H), 7.73-7.70 (m, 2H), 7.56(dd, 1H), 7.52 (t, 1H), 7.43 (dd, 1H), 3.12 (s, 3H), 2.70 (s, 3H), 1.98(s, 6H).

EXAMPLE 802-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)4-pyridin-3-yl-1,3-thiazol-2-yl]propan-2-ol

Step 1: ethyl4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-pyridin-3-yl-1,3-thiazole-2-carboxylate

Prepared according to the procedure described for EXAMPLE 1 using3-pyridinecarboxaldehyde in step 1 and ethyl thiooxamate in step 5.Flash chromatography (Hexane:EtOAc, 50:50-0:100) afforded the titlecompound.

Step 2:2-[4-(3-(6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-pyridin-3-yl-1,3-thiazol-2-yl]propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide. Flash chromatography (CH₂Cl₂:MeOH, 96:4) afforded the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.86-8.85 (m, 2H), 8.49 (dd, 1H), 8.39(dd, 1H), 8.24 (d, 1H), 8.05 (d, 1H), 7.97 (dt, 1H), 7.78-7.75 (m, 2H),7.54-7.50 (m, 2H), 7.45 (dt, 1H), 7.33 (dd, 1H), 5.26 (br s, OH), 2.67(s, 3H), 1.94 (s, 6H), 1.69 (s, 6H).

EXAMPLE 812-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-(1-oxidopyridin-3-yl)-1,3-thiazol-2-yl]propan-2-ol

Prepared according to the general procedure Oxid-2using EXAMPLE 80 asstarting material. Flash chromatography (CH₂Cl₂:MeOH, 95:5) afforded thetitle compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.43 (d, 1H), 8.26 (s,1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.58 (dd,1H), 7.50-7.43 (m, 5H), 5.12 (s, OH), 2.68 (s, 3H), 1.98 (s, 6H), 1.70(s, 6H).

EXAMPLE 821-(4-chlorophenyl)-1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}ethanol

Step 1: ethyl4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazole-2-carboxylate

Prepared according to the procedure described for EXAMPLE 1 usingQuinoline_(—)2 in step 1, 4-methylthiobenzaldehyde in step 2 and ethylthiooxamate in step 5. (step 3 is omitted).

Step 2:N-methoxy-N-methyl-4(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazole-2-carboxamide

To a solution of methoxymethylamine in THF (0.08M) at −78° C. was addedmethylmagnesium iodide (3M, ether, 1 eq) dropwise over 1 h. The reactionmixture was stirred at −78° C. for 10 min, a solution of ester from step1 was added and the reaction mixture was stirred at −78° C. for 2 h. Themixture was quenched with AcOH, diluted with NH₄Cl solution and EtOAc.The organic extracts were washed with brine, dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography(toluene:acetone, 80:20) to afforded the title compound.

Step 3:1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazol-2-yl)ethanone

Prepared according to the general procedure Cer-1 using methylmagnesiumiodide and amide from step 2.

Step 4:1-(4-chlorophenyl)-1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylthio)phenyl]-1,3-thiazol-2-yl}ethanol

Prepared according to the general procedure Cer-1 using4-chlorophenylmagnesium bromide and methylketone from step 3. Flashchromatography (CH₂Cl₂:MeOH, 96:4) afforded the title compound.

Step 5:1-(4-chlorophenyl)-1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}ethanol

Prepared according to the general procedure Oxid-1 using sulfide fromstep 4 as starting material. Flash chromatography (CH₂Cl₂:MeOH, 99:1)afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1), 8.07 (d, 1H), 7.95 (dd, 2H), 7.90 (t, 1H), 7.83 (dd, 2H), 7.76 (dd,1H), 7.71 (dd, 2H), 7.62 (dt, 1H), 7.56 (dd, 1H), 7.50 (t, 1H), 7.40(dd, 2H), 6.05 (s, OH), 3.12 (s, 3H), 2.72 (s, (s, 3H), 1.98 (s, 6H).

The following compounds (Table 2) were prepared according to theprocedure described previously (Ex. 1-80). Indicated is their respective(M+1)⁺ value obtained from a low resolution mass spectrometer underelectron-spray ionization conditions. TABLE 2 ESI- LRMS EX. Chemicalname (M + 1)⁺ 83 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[3- 639.3(methylsulfonyl)phenyl]-4-phenyl-1,3-thiazol-5- yl}phenyl)quinoline 842-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1- 577.2(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol 85 2-[4-(4-fluorophenyl)-5-(3-{6-[1-methyl-1-561.2 (methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol 868-{3-[4-(4-chlorophenyl)-2-quinolin-5-yl-1,3-thiazol- 646.25-yl]phenyl}-6-[1-methyl-1- (methylsulfonyl)ethyl]quinoline 872-{3-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1- 653.5(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol 882-{3-[4-(3-chloro-4-fluorophenyl)-5-(3-{6-[1-methyl- 670.91-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol 892-{3-[4-[3,4-bis(difluoromethoxy)phenyl]-5-(3-{6-[1- 751.3methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol 90N-{5-(3-{6-[1-methyl-1- 619.7(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide 91N-{5-(3-{6-[1-methyl-1- 655.4(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}pyridin-4- amine 922-[5-(3-{6-[1-methyl-1- 543.9(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-pyridin-4-yl-1,3-thiazol-2-yl]propan-2-ol 93 2-[5-(3-{6-[1-methyl-1-560.7 (methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-(1-oxidopyridin-4-yl)-1,3-thiazol-2-yl]propan-2-ol 942-[5-(4-chlorophenyl)-4-(3-{6-[1-methyl-1- 577.2(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol 952-{3-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1- 653.6(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol 966-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(1H- 471.1tetrazol-5-yl)pyridin-3-yl]phenyl}quinoline

EXAMPLE 976-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]thien-2-yl}phenyl)quinoline

Step 1: 2-bromo-3-[4-(methylthio)phenyl]thiophene

Prepared according to the general procedure Coupling-1 using4-methylthiobenzeneboronic acid and 3-bromothiophene. Flashchromatography (CH₂Cl₂) afforded the title compound.

Step 2: 4(2-bromothien-3-yl)phenyl methyl sulfone

Prepared according to the general procedure Oxid-1 using sulfide fromstep 1 as starting material.

Step 3:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]thien-2-yl}phenyl)quinoline

Prepared according to the general procedure Coupling-1 usingQuinoline_(—)4 and 3-bromothiophene from step 2 as starting material.Flash chromatography (toluene:EtOAc; 70:30) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.45 (dd, 1H), 8.25 (d,1H), 8.03 (d, 1H), 7.89 (d, 2H), 7.70 (m, 2H), 7.62 (m, 3H), 7.55 (dd,1H), 7.47 (t, 1H), 7.37 (m, 1H), 7.32 (d, 1H), 3.08 (s, 3H), 2.70 (s,3H), 1.95 (s, 6H).

EXAMPLE 981-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)ethanone

Step 1:8-(2′-bromo-1,1′-biphenyl-3-yl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to the general procedure Coupling-1 usingQuinoline_(—)4 and 1,2-dibromobenzene as starting material. Flashchromatography (Hex:EtOAc; 50:50) afforded the title compound.

Step 2:1-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)ethanone

Prepared according to the general procedure Coupling-1 using bromidefrom step 1 and 4-acetylbenzeneboronic acid as starting material. Flashchromatography (Hex:EtOAc; 50:50) afforded the title compound.

¹H NMR (500 MHz, Benzene-d₆): δ 8.81 (d, 1H), 7.93 (d, 1H), 7.85 (s,1H), 7.80 (m, 3H), 7.75 (s, 1H), 7.61 (m, 2H), 7.38 (m, 7H), 6.87 (dd,1H), 2.35 (s, 3H), 2.05 (s, 3H), 1.65 (s, 6H).

+ESI (M+1) 520.2

EXAMPLE 992-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)propan-2-ol

Step 1: 1-(2′-bromo-1,1′-biphenyl-4-yl)ethanone

Prepared according to the general procedure Coupling-1 using4-acetylbenzeneboronic acid and 1,2-dibromobenzene as starting material.Flash chromatography (Hex:EtOAc; 95:5) afforded the title compound.

Step 2: 2-(2′-bromo-1,1′-biphenylyl)propan-2-ol

Prepared according to the general procedure Cer-1 using methyl magnesiumbromide and ketone from step 1 as starting material. Flashchromatography (Hex:EtOAc; 90:10) afforded the title compound.

Step 3:2-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)propan-2-ol

Prepared according to the general procedure Coupling-1 usingQuinoline_(—)4 and bromide from step 2 as starting material. Flashchromatography (Hex:EtOAc; 50:50) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.45 (dd, 1H), 8.27 (d,1H), 8.01 (d, 1H), 7.68 (d, 1H), 7.62 (br s, 1H), 7.55 (m, 2H), 7.48 (m,3H), 7.42 (d, 2H), 7.38 (t, 1H), 7.21 (m, 3H).

+ESI (M+1) 536.8

EXAMPLE 1006-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-oxidopyridin-3-yl]phenyl}quinoline

Prepared according to the general procedure Coupling-1 usingQuinoline_(—)4 and Pyr_(—)11 as starting material. Flash chromatography(EtOAc:EtOH; 90:10) and crystallisation from EtOAc/ether afforded thetitle compound.

The following compounds (Table 3) were prepared according to the generalprocedure Coupling_(—)1 using Quinoline 4 and intermediates describedpreviously or commercial products (Commercial). Indicated is theirrespective (M+1)⁺ value obtained from a low resolution mass spectrometerunder electron-spray ionization conditions. TABLE 3 ESI-LRMS EX.intermediate Chemical name (M + 1)⁺ 101 Pyr_16-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5- 573.1[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3- yl}phenyl)quinoline 102Pyr_2 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5- 573.6[3-(methylsulfonyl)phenyl]-1-oxidopyridin-3- yl}phenyl)quinoline 103Pyr_3 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5- 573.2[2-(methylsulfonyl)phenyl]-1-oxidopyridin-3- yl}phenyl)quinoline 104Pyr_4 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2- 557.1[4-(methylsulfonyl)phenyl]pyridin-3- yl}phenyl)quinoline 105 Pyr_56-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3-(1-oxido- 495.15-phenylpyridin-3-yl)phenyl]quinoline 106 Pyr_68-{3-[5-(3,5-dichlorophenyl)-1-oxidopyridin-3- 563.1/565.1yl]phenyl}-6-[1-methyl-1- (methylsulfonyl)ethyl]quinoline 107 Pyr_78-{3-[5-(3,4-dimethoxyphenyl)-1-oxidopyridin- 555.13-yl]phenyl}-6-[1-methyl-1- (methylsulfonyl)ethyl]quinoline 108 Pyr_86-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5- 501.1(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxidopyridin-3- yl]phenyl}quinoline109 Pyr_9 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5- 501.1(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxidopyridin- 3-yl]phenyl}quinoline110 Pyr_10 8-{3-[6-(benzyloxy)-5-(3-methyl-1,2,4-oxadiazol- 591.25-yl)pyridin-3-yl]phenyl}-6-[1- methyl-1-(methylsulfonyl)ethyl]quinoline111 Pyr_12 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6- 573.3[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3- yl}phenyl)quinoline 112Pyr_13 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5- 573.3[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2- yl}phenyl)quinoline 113Pyr_14 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[3- 625.3[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-2-yl]phenyl}quinoline 114 Pyr_151-(4-chlorophenyl)-3-(3-{6-[1-methyl-1- 529.1(methylsulfonyl)ethyl]quinolin-8- yl}phenyl)pyridin-2(1H)-one 115 Pyr_166-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5- 501.1(2-methyl-2H-tetraazol-5-yl)-1-oxidopyridin- 3-yl]phenyl}quinoline 116Het_1 N-isopropyl-5-(3-{6-[1-methyl-1- 647.4(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2- carboxamide 117 Commercial6-[1-methyl-1-(methylsulfonyl)ethyl]-8- 478.1(1,1′:2′,1″-terphenyl-3-yl)quinoline 118 Phe_16-[1-methyl-1-(methylsulfonyl)ethyl]-8-[4″- 556.2(methylsulfonyl)-1,1′:2′,1″-terphenyl-3- yl]quinoline 119 Phe_26-[1-methyl-1-(methylsulfonyl)ethyl]-8-[2′-(5- 484.2methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3- yl]quinoline 120 Phe_3methyl 3-{6-[1-methyl-1- (methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′- carboxylate 121 Commercial6-[1-methyl-1-(methylsulfonyl)ethyl]-8- 478.2(1,1′:4′,1″-terphenyl-3-yl)quinoline 122 Commercial6-[1-methyl-1-(methylsulfonyl)ethyl]-8- 478.2(1,1′:3′,1″-terphenyl-3-yl)quinoline 123 Phe_4 2-[5-(3′-{6-[1-methyl-1-542.0 (methylsulfonyl)ethyl]quinolin-8-yl}-1,1′-biphenyl-2-yl)-1,3-thiazol-2-yl]propan-2-ol 124 Phe_56-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3′-(1- 495.1oxidopyridin-4-yl)-1,1′-biphenyl-3-yl]quinoline

EXAMPLE 1255-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one

A solution of EXAMPLE 110 (1.0 eq) in CH₂Cl₂/TFA (2:1, 0.06M) wasstirred at r.t. for 2 h, volatiles evaporated, diluted with EtOAc,washed with a solution of Na₂CO₃ and brine. The organic extracts weredried over MgSO₄, filtered and concentrated. Stirring in EtOAc-andisolation by filtration provided the title compound.

¹H NMR (500 MHz, DMSO-d₆): δ 8.92 (dd, 1H), 8.62 (d, 1H), 8.51 (dd, 1H),8.27 (d, 1H), 8.17 (s, 1H), 8.03 (d, 1H), 7.86 (s, 1H), 7.68 (d, 1H),7.62-7.55 (m, 3H), 2.80 (s, 3H), 2.37 (s, 3H), 1.92 (s, 6H).

EXAMPLE 1266-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6-[4-(methylsulfonyl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}phenyl)quinoline

To a solution of the alphabromoketone from EXAMPLE 1, step 4 (1.0 eq) inDMF (0.1M) was added 2-aminothiazole (1.6 eq). The mixture was heated at120° C. for 1 h, cooled, diluted with water, saturated NaHCO₃ solutionand EtOAc. The organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (Toluene:EtOAc, 1:3) to afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 9.02 (dd, 1H), 8.50 (dd, 1H), 8.32 (d,1H), 8.26 (d, 1H), 8.08-8.05 (m, 4H), 7.92 (d, 2H), 7.85 (d, 1H), 7.69(t, 1H), 7.62-7.59 (m, 2H), 7.36 (d, 1H), 3.15 (s, 3H), 2.74 (s, 3H),2.01 (s, 6H).

EXAMPLE 1276-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl}phenyl)quinoline

Prepared according to the procedure described for EXAMPLE 126 and using2-aminopyridine as starting material. Flash chromatography(Toluene:EtOAc, 1:3) afforded the title compound.

¹H NMR (500 M, acetone-d₆): δ 9.00 (dd, 1H), 8.50. (d, 1H), 8.48 (dd,1H), 8.32 (d, 1H), 8.27 (d, 1H), 8.14 (d, 2H), 8.07 (t, 1H), 7.94-7.92(m, 3H), 7.76 (t, 1H), 7.67 (d, 1H), 7.62-7.59 (m, 2H), 7.39 (dd, 1H),7.03 (dt, 1H), 3.16 (s, 3H), 2.74 (s, 3H), 2.01 (s, 6H).

EXAMPLE 128[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylthio)-1,1′:2′,1″-terphenyl-4′-yl]methanol

Step 1:2-bromo-3′-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′-biphenyl-4-carbaldehyde

Prepared according to the general procedure Coupling_(—)1 usingQuinoline_(—)4 and 3,4-dibromobenzaldehyde as starting materials. Flashchromatography (hexane:EtOAc, 9:1 to 1:1) afforded the title compound asfoam.

Step 2:3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylthio)-1,1′:2′,1″-terphenyl-4′-carbaldehyde

Prepared according to the general procedure Coupling_(—)1 using aldehydefrom step 1 and 4-methylthiobenzeneboronic acid as starting materials.Flash chromatography (hexane:EtOAc, 3:2 to 1:1) afforded the titlecompound.

Step 3:[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylthio)-1,1′:2′,1″-terphenyl-4′-yl]methanol

To a solution of aldehyde from step 2 in EtOH: THF (4:1, 0.05M) at 0° C.was added NaBH₄ (1 eq). The reaction mixture was stirred 1 h at 0° C.,quenched with a solution of NH₄Cl and diluted with ether. The organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography(hexane:EtOAc, 1:1 to 1:9) to afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.43 (d, 1H), 8.25 (d,1H), 7.88 (d, 1H), 7.67 (d, 1H), 7.56 (dd, 1H), 7.55-7.46 (m, 4H), 7.42(t, 1H), 7.29-7.18 (m, 5H), 4.76 (d, 2H), 4.33 (t, 1H), 2.70 (s, 3H),2.474 (s, 3H), 1.97 (s, 6H).

EXAMPLE 129[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]methanol

Prepared according to the general procedure Oxid-1 using Example 128 asstarting material. The title compound was isolated as white foam.

¹H NMR (500 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.44 (d, 1H), 8.26 (d,1H), 7.98 (d, 1H), 7.85 (d, 2H), 7.68 (d, 1H), 7.58-7.52 (m, 7H), 7.41(t, 1H), 7.25 (d, 1H), 4.79 (d, 2H), 4.4 (t, 1H), 3.03 (s, 3H), 2.71 (s,3H), 1.97 (s, 6H).

EXAMPLE 1302-[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]propan-2-ol

Prepared according to the general procedure Cer-1 using Example 120 asstarting material. The residue was purified by flash chromatography(hexane:EtOAc, 1:1 to 3:7) to afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d,1H), 7.98 (d, 1H), 7.85 (d, 2H), 7.71-7.67 (m, 3H), 7.57-7.53 (m, 4H),7.40 (t, 1H), 7.23 (d, 1H), 4.24 (s, OH), 3.03 (s, 3H), 2.71 (s, 3H),1.97 (s, 6H), 1.63 (s, 6H).

EXAMPLE 1313-6{-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-carboxylicacid

To a solution of Example 120 in THF:MeOH (1:1, 0.05M) was added LiOH(2N, 5 eq). The reaction mixture was stirred at rt for 24 h, acidifiedto pH 2 with 1N HCl and diluted with EtOAc. The organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was sonicated in hexane/EtOAc and title product isolated byfiltration as a white powder.

¹H NMR (500 MHz, CD₃OD): δ 8.86 (dd, 1H), 8.44 (d, 1H), 8.22 (d, 1H),8.16 (dd, 1H), 8.12 (d, 1H), 7.87 (d, 2H), 7.84 (d, 1H), 7.69 (d, 1H),7.61-7.54 (m, 4H), 7.46 (t, 1H), 7.43 (s, 1H), 7.32 (d, 1H), 4.79 (d,2H), 4.4 (t, 1H), 3.04 (s, 3H), 2.74 (s, 3H), 1.98 (s, 6H).

EXAMPLE 1326-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]-1-oxidopedin-3-yl}phenyl)quinoline

Prepared according to the general procedure Oxid-2 using Example 104 asstarting material. The residue was sonicated in hexane/EtOAc and titleproduct isolated by filtration as a white powder.

¹H NMR (500 MHz, acetone-d₆): δ 8.92 (dd, 1H), 8.42 (dd, 1H), 8.35 (d,1H), 8.25 (d, 1H), 7.95 (d, 1H), 7.85 (d, 2H), 7.65 (d, 2H), 7.57-7.48(m, 5H), 7.36 (t, 1H), 7.21 (d, 1H), 3.02 (s, 3H), 2.70 (s, 3H), 1.96(s, 6H).

EXAMPLE 1338-{3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Step 1: methyl3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}benzoate

To a solution of Quinoline_(—)2 in CH₂Cl₂:MeOH (1:2, 0.03M) was addedNaCN (1.8 eq), AcOH (1 eq) followed by MnO₂ (8 eq). The reaction mixturewas stirred at rt for 24 h, filtered on Celite and diluted with water.The mixture was extracted with CH₂Cl₂ (3×). The organic extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash chromatography (hexane:EtOAc, 1:1) toafforded the title compound.

Step 2: 3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}benzoicacid

To a solution of ester from step 1 in TBF (0.08M) was added LiOH (2N, 5eq). The reaction mixture was stirred at rt for 5h, acidified with AcOH,diluted with water and extracted with CH₂Cl₂. The organic extracts werewashed with brine, dried over Na2SO4, filtered and concentrated. Thetitle compound was isolated by filtration from Hexane/ether as a solid.

Step 3:8-{3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

To a solution of acid from step 2 in DMF (0.05M) was added CDI (2 eq)and 4-fluoro-N′-hydroxybenzenecarboximidamide (2 eq). The reactionmixture was stirred at rt for 15 min and 18 h at 120° C. The reactionmixture cooled to rt, diluted with water and extracted with EtOAc. Theorganic extracts were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography(hexane:EtOAc, 20:80) to afforded the title compound.

¹H NMR (500 M acetone-d₆): δ 8.98 (dd, 1H), 8.64 (s, 1H), 8.55 (dd, 1H),8.39 (d, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 8.25 (dd, 2H), 8.08 (d, 1H),7.82 (t, 1H), 7.63 (dd, 1H), 7.39 (t, 2H), 2.79 (s, 3H), 2.05 (s, 6H).+ESI (M+1) 488.2.

EXAMPLE 1346-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline

Step 1: 4-chloro-3-(tributylstannyl)pyridine

To a solution of LDA (1.1 eq) in THF (0.05M) at −78° C. was added4-chloropyridine (1 eq). After 1.5 h tributyltin chloride (1.5 eq) wasadded and the reaction mixture was warmed at rt over 3 h. The reactionmixture was diluted with water and extracted with EtOAc. The organicextracts were washed with brine, dried over MgSO4, filtered andconcentrated. The residue was purified by flash chromatography(hexane:EtOAc, 95:5) to afforded the title compound.

+ESI (M+1) 525.3

Step 2:8-[3-(4-chloropyridin-3-yl)phenyl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to the general procedure Coupling_(—)3 usingQuinoline_(—)3 and the Aryltin from step 1 as starting materials. Flashchromatography (CH₂Cl₂:MeOH, 99:1) afforded the title compound.

Step 3:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline

Prepared according to the general procedure Coupling_(—)1 using4-methylthiobenzeneboronic acid and the chloropyridine from step 2 asstarting materials. Flash chromatography afforded the title compound.

¹H NMR (500 Mz, acetone-d₆): δ 8.91 (dd, 1H), 8.70 (s, 1H), 8.63 (d,1H), 8.44 (dd, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.76 (d, 1H), 7.58 (d,1H), 7.56 (dd, 1H), 7.49 (t, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 7.28 (d,2H), 7.23 (d, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 1.98 (s, 6H).

+ESI (M+1) 525.3

EXAMPLE 1353″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-carboxylicacid

Step 1:8-(2′-bromo-1,1′-biphenyl-3-yl)-6-[1-methyl-4-(methylsulfonyl)ethyl]quinoline

Prepared according to the general procedure Coupling_(—)1 usingQuinoline_(—)4 and 1,2-dibromobenzene as starting materials. Flashchromatography (hexane:EtOAc, 1:1) afforded the title compound.

Step 2:3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-carboxylicacid

Prepared according to the general procedure Coupling_(—)1 usingArylbromide from step 1 and 4-carboxybenzeneboronic acid as startingmaterials. Flash chromatography (CH₂Cl₂:MeOH, 9:1) afforded the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,2H), 8.07 (d, 2H), 7.96 (d, 1H), 7.83 (d, 1H), 7.68 (d, 1H), 7.62 (d,1H), 7.52 (m, 4H), 7.41 (d, 2H), 7.28 (d, 1H), 2.68 (s, 3H), 1.95 (s,6H). −ESI (M−1) 520.4

EXAMPLE 1362-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline

A solution of2-bromo-2-(3-(6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1-[4-(methylsulfonyl)phenyl]ethanonefrom EXAMPLE 1, step 4 in DMF (0.05M) and 1,2-diaminobenzene (2 eq) wasstirred at 130° C. for 18 h. The reaction mixture was cooled to rt,diluted with water and extracted with EtOAc. The organic extracts werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash chromatography (hexane:EtOAc, 1:1) toafforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.43 (dd, 1H), 8.29 (d,1H), 8.21 (m, 2H), 8.05 (d, 1H), 8.00 (d, 2H), 7.96 (d, 2H), 7.95 (m,3H), 7.85 (d, 1H), 7.70 (d, 1H), 7.58 (m, 2H), 3.10 (s, 3H), 2.72 (s,3H), 1.99 (s, 6H).

EXAMPLE 1376-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]pyrazin-2-yl}phenyl)quinoline

Step 1:8-[3-(3-chloropyrazin-2-yl)phenyl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to the general procedure Coupling_(—)1 usingQuinoline_(—)4 and 1,2-dichloropyrazine as starting materials. Flashchromatography (hexane:EtOAc, 3:7) afforded the title compound.

Step 2:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylthio)phenyl]pyrazin-2-yl}phenyl)quinoline

Prepared according to the general procedure Coupling_(—)1 using4-methylthiobenzeneboronic acid and the chloropyrazine from step 1 asstarting materials. Flash chromatography (hexane:EtOAc, 2:8) affordedthe title compound.

Step 3:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]pyrazin-2-yl}phenyl)quinoline

Prepared according to the general procedure Oxid-1 using thioether fromstep 2 as starting material. Flash chromatography (hexane:EtOAc, 2:8)afforded the title compound.

¹H NMR (500 MHz, DMSO-d₆): δ 8.86 (dd, 1H), 8.78 (d, 1H), 8.75 (d, 1H),8.45 (dd, 1H), 8.27 (d, 1H), 8.02 (d, 1H), 7.94 (d, 2H), 7.85 (d, 2H),7.83 (m, 2H), 7.60 (m, 1H), 7.39 (m, 1H), 7.25 (t, 1H), 3.09 (s, 3H),2.71 (s, 3H), 1.98 (s, 6H).+ESI (M+1) 558.1

The following compounds (Table 4) were prepared according to theprocedure described previously. Indicated is their respective (M+1)⁺value obtained from a low resolution mass spectrometer underelectron-spray ionization conditions. TABLE 4 ESI- LRMS EX. Chemicalname (M + 1)⁺ 138 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4- 557.1(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)quinoline 1396-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4- 573.3(methylsulfonyl)phenyl]-1-oxidopyridin-3- yl}phenyl)quinoline 1406-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[3- 525.0(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline 1418-[4′,5′-difluoro-4″-(methylthio)-1,1′:2′,1″-terphenyl-3- 560.1yl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline 1428-[4′,5′-difluoro-4″-(methylsulfonyl)-1,1′:2′,1″- 591.8terphenyl-3-yl]-6-[1-methyl-1- (methylsulfonyl)ethyl]quinoline 1438-(4″-fluoro-1,1′:2′,1″-terphenyl-3-yl)-6-[1-methyl-1- 496.1(methylsulfonyl)ethyl]quinoline 144 6,7-dichloro-2-(3-{6-[1-methyl-1-676.1 (methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline 1452-(4-chlorophenyl)-3-(3-{6-[1-methyl-1- 564.1(methylsulfonyl)ethyl]quinolin-8- yl}phenyl)quinoxaline 1462-{4-[3-(3-{6-[1-methyl-1- 588.0 (methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]phenyl}propan-2-ol 1472-[3,4-bis(difluoromethoxy)phenyl]-3-(3-{6-[1- 662.0methyl-1-(methylsulfonyl)ethyl]quinolin-8- yl}phenyl)quinoxaline 1484-[3-(3-{6-[1-methyl-1- 574.3 (methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]benzoic acid 149N-cyclopropyl-4-[3-(3-{6-[1-methyl-1- 613.4(methylsulfonyl)ethyl]quinolin-8- yl}phenyl)quinoxalin-2-yl]benzamide150 2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8- 544.2yl}phenyl)-3-(4-methylphenyl)quinoxaline 1512-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8- 530.2yl}phenyl)-3-phenylquinoxaline 1522-(4-fluorophenyl)-3-(3-{6-[1-methyl-1- 548.8(methylsulfonyl)ethyl]quinolin-8- yl}phenyl)quinoxaline 1532-{4-[3-(3-{6-[1-methyl-1- 536.8(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyrazin-2-yl]phenyl}propan-2-ol 1546-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4- 526.3(methylthio)phenyl]pyrazin-2-yl}phenyl)quinoline 1558-{3-[3-(4-fluorophenyl)pyrazin-2-yl]phenyl}-6-[1- 498.2methyl-1-(methylsulfonyl)ethyl]quinoline 1568-(3-{2-(2-ethylpyridin-4-yl)-4-[4- 668.3(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline 1572-(4-{5-(3-{6-[1-methyl-1- 697.5(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2- yl}phenyl)propan-2-ol

EXAMPLE 1585-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one

To a suspension of ketone from EXAMPLE 1, step 3 in MeOH (0.15M) at 0°C. was condensed NH₃ (30% volume) and added methyl propiolate (6 eq).The reaction mixture was heated in a pressure tube at 150° C. for 5 h,cooled to rt and concentrated to dryness. The residue was purified byflash chromatography (EtOH:EtOAc, 12:88) to afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 11.15 (br s, 1H), 8.87 (dd, 1H), 8.41(dd, 1H), 8.23 (d, 1H), 7.95 (d, 1H), 7.88 (dd, 2H), 7.72 (d, 1H), 7.69(dd, 2H), 7.63 (dt, 2H), 7.53 (m, 2H), 7.38 (t, 1H), 7.18 (dt, 1H), 6.59(d, 1H), 3.04 (s, 3H), 2.69 (s, 3H), 1.94 (s, 6H).

EXAMPLE 1591-methyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one

To a solution of EXAMPLE 158 in DMF (0.05M) at 0° C. was added NaH (1.1eq) followed by MeI (6 eq). The reaction mixture was stirred at rt for 1h, diluted with NH₄Cl solution and extracted with EtOAc. The organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography(hexane:EtOAc, 70:30, then EtOH:EtOAc, 12:88) to afforded the titlecompound and EXAMPLE 160.

¹H NMR (500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.45 (dd, 1H), 8.26 (d,1H), 7.97 (m, 3H), 7.74 (d, 2H), 7.59 (m, 3H), 7.46 (t, 1H), 7.30 (t,1H), 7.12 (d, 1H), 6.60 (d, 1H), 3.26 (s, 3H), 3.00 (s, 3H), 2.74 (s,3H), 2.00 (s, 6H).

EXAMPLE 1608-(3-{6-methoxy-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to the procedure described for EXAMPLE 159.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.00 (d, 1H), 7.90 (d, 1H), 7.87 (d, 2H), 7.79 (d, 2H), 7.71 (dt,1H), 7.61 (t, 1H), 7.56 (dd, 1H), 7.48 (t, 1H), 7.29 (dt, 1H), 6.96 (d,1H), 4.03 (s, 3H), 3.10 (s, 3H), 2.71 (s, 3H), 1.97 (s, 6H).

EXAMPLE 1618-(3-{6-(difluoromethoxy)-2-(4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to procedure described for EXAMPLE 159 but usingethyl bromodifluoroacetate as electrophile. Flash chromatography(hexane:EtOAc, 70:30, then EtOH:EtOAc, 12:88) afforded the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.45 (dd, 1H), 8.27 (d,1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.89 (d, 2H), 7.87 (t, 1H), 7.80 (d,2H), 7.76 (dt, 1H), 7.65 (t, 1H), 7.57 (dd, 1H), 7.51 (t, 1H), 7.34 (dt,1H), 7.22 (d, 2H), 3.11 (s, 3H), 2.71 (s, 3H), 1.97 (s, 6H).

EXAMPLE 1628-(3-{6-[(4-fluorobenzyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to procedure described for EXAMPLE 159 but using4-fluorobenzyl bromide as electrophile. Flash chromatography(hexane:EtOAc, 70:30, EtOH:EtOAc, 12:88, EtOH:EtOAc, 5:95) afforded thetitle compound and EXAMPLE 162.

¹H NMR (500 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.88 (d, 2H), 7.78 (d, 2H), 7.72 (dt,1H), 7.61 (m, 3H), 7.56 (dd, 1H), 7.47 (t, 1H), 7.30 (dt, 1H), 7.19 (t,2H), 7.02 (d, 1H), 5.53 (s, 2H), 3.10 (s, 3H), 2.71 (s, 3H), 1.97 (s,6H).

EXAMPLE 1631-(4-fluorobenzyl)-5-(3-{6-[1-methyl-i-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4(methylsulfonyl)phenyl]pyridin-2(1H)-one

Prepared according to the procedure described for EXAMPLE 162.

¹H NMR (500 MHz, acetone-d₆): δ 8.93 (dd, 1H), 8.44 (dd, 1H), 8.25 (d,1H), 7.92 (d, 1H), 7.82 (d, 2H), 7.68 (d, 1H), 7.57 (m, 2H), 7.47 (d,2H), 7.43 (s, 1H), 7.29 (t, 1H), 7.14 (d, 2H), 6.98 (t, 2H), 6.92 (m,2H), 6.73 (d, 1H), 5.18 (br s, 2H), 2.99 (s, 3H), 2.73 (s, 3H), 1.98 (s,6H).

EXAMPLE 1645-(4fluorophenyl)-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one

Step 1:2-(4-fluorophenyl)-1-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)ethanone

Prepared according to the procedure described for EXAMPLE 1, step 1-2,using Quinoline_(—)2 in step 1 and 4-fluorobenzaldehyde in step 2. Flashchromatography (Hexane:EtOAc, 40:60) afforded the title compound.

Step 2:5-(4-fluorophenyl)-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one

Prepared according to the procedure described for EXAMPLE 158. Flashchromatography (EtOH:EtOAc, 12:88) afforded the title compound.

¹H NMR (500 MHz, Acetone/Chlooroform=2:1): δ 8.89 (dd, 1H), 8.39 (dd,1H), 8.22 (d, 1H), 7.88 (s, 1H), 7.79 (d, 2H), 7.62 (s, 1H), 7.57 (d,1H), 7.54 (dd, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.22 (m, 2H), 7.02 (t,2H), 6.52 (d, 2H), 2.67 (s, 3H), 1.96 (s, 6H).

EXAMPLE 1655-(4-fluorophenyl)-1-methyl-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one

Prepared according to the procedure described for EXAMPLE 159 usingEXAMPLE 164 as starting material. The residue was purified by flashchromatography (hexane:EtOAc, 60:40, then EtOH:EtOAc, 8:92) to affordedthe title compound and EXAMPLE 166.

¹H NMR (500 MHz, acetone-d₆): δ 8.97 (dd, 1H), 8.47 (dd, 1H), 8.31 (d,1H), 8.05 (d, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.77 (d, 1H), 7.60 (dd,1H), 7.50 (m, 2H), 7.31 (d, 1H), 7.26 (m, 2H), 6.98 (t, 2H), 6.54 (d,2H), 3.38 (s, 3H), 2.73 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H).

EXAMPLE 1668-{3-[3-(4-fluorophenyl)-6-methoxypyridin-2-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline

Prepared according to the procedure described for EXAMPLE 165.

¹H NMR (500 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.44 (dd, 1H), 8.27 (dd,1H), 7.96 (dd, 1H), 7.80 (t, 1H), 7.75 (d, 1H), 7.72 (dt, 1H), 7.57 (dd,1H), 7.48 (dt, 1H), 7.41 (t, 1H), 7.32 (m, 2H), 7.11 (t, 2H), 6.87 (d,1H), 4.01 (s, 3H), 2.70 (s, 3H), 1.98 (s, 6H).

EXAMPLE 167N-cyclopropyl-8-(3-{2-(1-hydroxy-1-methylethyl)4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline-6-carboxamide

Step 1:2-{5-(3-bromophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol

Prepared according to the procedure described for EXAMPLE 71 using3-bromo benzaldehyde as precursor. Flash chromatography (Hexane:EtOAc,50:50-20:80) afforded the title compound.

Step 2:2-(5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol

Prepared according to the procedure described for Quinoline_(—)4 usingbromide from step 1. Flash chromatography (Hexane:EtOAc, 50:50) affordedthe title compound.

Step 3:N-cyclopropyl-8-(3-{2-(1-hydroxy-l-methylethyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline-6-carboxamide

Prepared according to the procedure Coupling-1 using boronic ester fromstep 2 and Quinoline_(—)5 as starting material. Flash chromatography(Hex:EtOAc; 10:90) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.94 (dd, 1H), 8.48 (br s, 1H), 8.45 (d,1H), 8.22 (d, 1H), 8.16 (s, NH), 7.94 (m, 4H), 7.81 (m, 2H), 7.62 (t,1H), 7.59 (d, 1H), 7.50 (d, 1H), 5.21 (s, OH), 3.19 (s, 3H), 3.00 (s,1H), 1.71 (s, 6H), 0.80 (m, 2H), 0.68 (m, 2H).

EXAMPLE 1688-(3-{2-(1-hydroxy-1-methylethyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline-6-carboxylicacid

Prepared according to the procedure Coupling-1 using boronic ester fromEXAMPLE 167, step 2 and 8-bromoquinoline-6-carboxylic acid fromQuinoline_(—)5, step 1 as starting material. Flash chromatography(CH₂Cl₂:MeOH; 90:10) afforded the title compound.

¹H NMR (500 MHz, CD₃OD): δ 9.35 (d, 1H), 9.17 (dd, 1H), 9.03 (br s, 1H),8.43 (br s, 1H), 8.18 (m, 1H), 7.93 (d, 2H), 7.87 (d, 2H), 7.69 (m, 4H),3.40 (s, OH), 3.17 (s, 3H), 1.71 (s, 6H). +ESI, Q1 (M+1) 545.2

EXAMPLE 1692-[4-[4-(methylsulfonyl)phenyl]-5-(3-{6-[1-methyl-1-(1H-tetraazol-5-yl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol

Step 1: 8-bromo-6-[1-methyl-1-(1H-tetraazol-5-yl)ethyl]quinoline

To a solution of Quinoline_(—)6 in Xylenes (0.2M) was added tributyltinchloride (5 eq) and sodium azide (5 eq). The reaction mixture wasstirred at 135° C. for 2 days. The reaction mixture was diluted withNaOH 5N and the solid isolated by filtration washing withbenzene/hexane. The material was suspended and stirred in MeOH/Et₂O andthe title product isolated by filtration.

Step 2:2-[4-[4-(methylsulfonyl)phenyl]-5-(3-{6-[1-methyl-1-(1H-tetraazol-5-yl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol

Prepared according to the procedure Coupling-1 using boronic ester fromEXAMPLE 167, step 2 and tetrazole from step 1 as starting material.Flash chromatography (CH₂Cl₂:MeOH:NH₄OH; 90:10:5) afforded the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.82 (dd, 1H), 8.33 (dd, 1H), 7.93 (m,4H), 7.87 (d, 1H), 7.76 (br s, 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.50 (m,2H), 7.42 (d, 1H), 5.51 (br s, NH), 3.32 (s, OH), 3.15 (s, 3H), 1.98 (s,6H), 1.71 (s, 6H). +ESI, Q1 (M+1) 611.3

EXAMPLE 1701,1,1,3,3,3-hexafluoro-2-[8-(3-{2-(1-hydroxy-1-methylethyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinolin-6-yl]propan-2-ol

Step 1: 3-bromo-4-(hexafluoro-2-hydroxyisopropyl)aniline

To a solution of 4-(hexafluoro-2-hydroxyisopropyl)aniline in DMF (0.08M)was added NBS (1.1 eq). The reaction mixture was stirred at rt for 1 h,diluted with water and extracted with EtOAc. The organic extracts werewashed with brine, dried over MgSO₄, filtered and concentrated to affordthe title compound.

Step 2: 2-(8-bromoquinolin-6-yl)-1,1,1,3,3,3-hexafluoropropan-2-of

Prepared according to the procedure described for Quinoline-5, step 1using aniline from step 1 as starting material. Flash chromatography(Hex:EtOAc; 80:20 to 50:50) afforded the title compound.

Step 3:1,1,1,3,3,3-hexafluoro-2-[8-(3-{2-(1-hydroxy-1-methylethyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinolin-6-yl]propan-2-ol

Prepared according to the procedure Coupling-1 using boronic ester fromEXAMPLE 167, step 2 and quinoline from step 1 as starting material.Flash chromatography (Hex:EtOAc; 80:20 to 50:50) afforded the titlecompound.

¹H NMR (500 MHz, acetone-d₆): δ 8.98 (d, 1H), 8.60 (d, 1H), 8.46 (s,1H), 8.13 (s, 1H), 7.94 (m, 4H), 7.82 (m, 2H), 7.66 (dd, 1H), 7.61 (t,1H), 7.51 (d, 1H), 5.21 (s, OH), 3.12 (s, 3H), 2.87 (s, OH), 2.05 (s,3H), 1.72 (s, 6H). +ESI, Q1 (M+1) 667.4

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt, wherein S₁, S₂, and S₃ areindependently
 1. H,
 2. —OH,
 3. halogen,
 4. —C₁-C₆alkyl,
 5. —O—C₁-C₆alkyloptionally substituted with 1, 2 or 3 halogens, or —CN; R₁ is 1.—(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl) group, optionally substituted with 1,2 or 3 substituents; wherein each substituent is independently ahalogen, —OH and —CN,
 2. —C(O)—O-aryl,
 3. —C(O)—NH-aryl, 4.—C(O)—NH-heterocycle or N-oxide thereof,
 5. —C(O)—NH—C₁-C₆alkyl, 6.—C(O)—NH-cycloC₃-C₆alkyl,
 7. —C₁-C₆alkyl, optionally substituted with 1to 6 halogens and 1 hydroxy,
 8. —COOH,
 9. —C₁-C₆alkyl-COOH, 10.—O—C₁-C₆alkyl,
 11. —cycloC₃-C₆alkyl,
 12. —C₃-C₆alkyl-heterocycle, 13.aryl,
 14. heterocycle,
 15. carbonyl,
 16. carbamoyl, or 17.—SO_(n)—(C₁-C₆alkyl); each n is independently 0, 1, or 2; Ar₁ and Ar₂are each independently an aryl or heterocycle or an N-oxide thereof; R₂is
 1. Hydrogen,
 2. aryl optionally substituted with 1, 2 or 3substituents selected from halogen,
 3. heterocycle optionallysubstituted with 1, 2 or 3 halogens,
 4. —C₁-C₆alkyl optionallysubstituted with 1, 2 or 3 substituents selected from hydroxy andhalogen,
 5. —COOH,
 6. 1, 2 or 3 halogens,
 7. —SO_(n)—(C₁-C₆alkyl), 8.—N(H)—S(O)_(n)—C₁-C₆alkyl,
 9. —O—C₁-C₆alkyl substituents each optionallysubstituted with 1, 2 or 3 halogens,
 10. —C(O)—N(H)—C₃-C₆cycloalkyl, or11. —C(O)—C₁-C₆alkyl; R₃ is
 1. Hydrogen,
 2. —C₁-C₆alkyl optionallysubstituted with hydroxy, —S(O)_(n)C₁-C₆alkyl, heterocycle, or 1, 2, 3,4, 5 or 6 halogens,
 3. aryl or C₆-C_(12cyclo)alkyl optionallysubstituted with phenyl, —C₁-C₆alkyl, —S(O)_(n)C₁-C₆alkyl,—C(O)—O—C₁-C₆alkyl, —COOH, hydroxy-C₁-C₆alkyl- or 1, 2 or 3 halogens, 4.heterocycle or optionally substituted with 1, 2 or 3 substituentsindependently selected from phenyl, halogen, C₁-C₆alkyl,hydroxyC₁-C₆alkyl, —COOH, —C(O)—O—C₁-C₆alkyl,
 5. amino, 6.—C(O)—O—C₁-C₆alkyl,
 7. —C₁-C₆alkyl-O-phenyl optionally substituted with1, 2 or 3 halogens,
 8. —C₁-C₆alkyl-phenyl optionally substituted with 1or 2 substituents selected from hydroxy and halo,
 9. —COOH,
 10. Halogen,11. —SO_(n)—(C₁-C₆alkyl),
 12. —N(H)—S(O)_(n)—C₁-C₆alkyl optionallysubstituted with 1, 2 or 3 halogen,
 13. —N(H)—C(O)—C₁-C₆alkyl, 14.—N(H)-heterocycle optionally substituted with 1, 2 or 3 halogens, 15.—N(H)-aryl optionally substituted with 1, 2 or 3 halogens, 16.—N(H)—C₁-C₆alkyl optionally substituted with 1, 2 or 3 halogens, 17.—C(O)—N(H)—C₁-C₆alkyl optionally substituted with 1, 2 or 3 halogens,18. —C(O)—NH—C₃-C₆cycloalkyl,
 19. —O—C₁-C₆alkyl optionally substitutedwith 1, 2 or 3 halogens or phenyl optionally substituted with 1, 2, or 3halogen; R₄ is
 1. H,
 2. Halogen,
 3. —CN
 4. —C₁-C₆alkyl,
 5. —O—C₁-C₆alkyloptionally substituted with 1, 2 or 3 halogens,
 6. —C₁-C₆alkyl-phenylwith phenyl optionally substituted with halogen, or
 7. Oxo.
 2. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein Ar₁ is pyridine or pyridinone or an N-oxide thereof. 3.A compound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein Ar₂ is phenyl, oxadiazole or thiadiazole.
 4. A compoundaccording to claim 3, or a pharmaceutically acceptable salt thereof,wherein R₁ is —(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl); and R₂ is—SO_(n)—C₁-C₆alkyl.
 5. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein Ar₁ is phenyl.
 6. Acompound according to claim 5, or a pharmaceutically acceptable saltthereof, wherein Ar₂ is phenyl, oxadiazole, thiadiazole, pyridine orpyridinone or an N-oxide thereof.
 7. A compound according to claim 6, ora pharmaceutically acceptable salt thereof, wherein R₁ is—(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl); and R2 is —SO_(n)—C₁-C₆alkyl.
 8. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein Ar₁ is thiazole or oxazole.
 9. The compound accordingto claim 8, or a pharmaceutically acceptable salt thereof, wherein Ar₂is phenyl, pyridine or pyridinone or an N-oxide thereof.
 10. Thecompound according to claim 9, or a pharmaceutically acceptable saltthereof, wherein R₁ is —(C₁-C₆alkyl)-SO_(n)—(C₁-C₆alkyl); and R2 is—SO_(n)—C₁-C₆alkyl.
 11. The compound according to claim 1 of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein: Ar₁ is phenyl,pyridine, pyridinone, pyrimidyl, thiophene, thiazole, triazole,tetrazole, oxazole, thiaphendiazole, pyridindiazole, imidazothiazole orquinoxaline or an N-oxide thereof; and Ar₂ is phenyl, pyridine,pyridinone, oxadiazole or thiadiazole or an N-oxide thereof.
 12. Acompound according to claim 11, or a pharmaceutically acceptable saltthereof, wherein: R₂ is phenyl, —COOH, —C₁-C₆alkyl, —C₁-C₆alkoxy, monoor di-halo-C₁-C₆alkoxy, hydroxyC₁-C₆alkyl, or —SO_(n)—(C₁-C₆alkyl) or 1,2 or 3 halogens;.
 13. A compound according to claim 12, or apharmaceutically acceptable salt thereof, wherein: R₃ is Hydrogen,amino, biphenyl, N-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-yl,N-(tert-butoxycarbonyl)azetidin-3-yl,N-(tert-butoxycarbonyl)pyrrolidin-3-yl, 3-chloro-4-fluorophenyl,4-chlorophenoxymethyl, 2-chlorophenyl, 4-chlorophenyl, ethoxycarbonyl,furan-2-yl, furan-3-yl, imidazol-2-yl, indan-1-yl, indan-2-yl,1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl,1H-indol-6-yl, 1H-indol-7-yl, isoquinolin-1-yl, isoquinolin-4-yl,isoquinolin-5-yl, isoquinolin-8-yl, isoxazol-3-yl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, methyl,1-methyl-1Hpyrazol-3-yl, 1-methyl-1Hpyrazol-4-yl,1-methyl-1Hpyrazol-5-yl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-methylpyridin-5-yl, methylsulfonylmethyl, 2-methylsulfonylphenyl,3-methylsulfonylphenyl, 4-methylsulfonylphenyl, morpholin-4-ylmethyl,phenyl, pyrazinyl, 1Hpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 3-pyridinylmethyl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, quinolin-4-yl, quinolin-5-yl, quinolin-8-yl,5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl,5,6,7,8-tetrahydro-5Hbenzo[a][7]annulen-5-yl,5,6,7,8-tetrahydro-5Hbenzo[a][7]annulen-6-yl, tetrahydrofuran-2-yl,1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl,1,3-thiazol-2-yl, 1,3-thiazol-5-yl, thiophen-2-yl and thiophen-2-yl. 14.A compound according to claim 11, or a pharmaceutically acceptable saltthereof, wherein: Ar₁ is thiazole; Ar₂ is phenyl; and R₂ is—SO₂—C₁-C₆alkyl or halogen or C₁-C₆alkyl optionally substituted withhydroxy or 1-3 halogens.
 15. A compound according to claim 14 or apharmaceutically acceptable salt thereof, wherein: R₃ is Hydrogen or—C₁-C₆alkyl optionally substituted with hydroxy, —S(O)_(n)C₁-C₆alkyl, or1-6 halogens.
 16. A compound according to claim 11, or apharmaceutically acceptable salt thereof, wherein Ar₁ is pyridine or anN-oxide thereof; Ar₂ is oxadiazole; and R₂ is
 1. —C₁-C₆alkyl optionallysubstituted with hydroxy, —S(O)_(n)C₁-C₆alkyl, or 1-3 substituentshalogens,
 2. —N(H)—C(O)—C₁-C₆alkyl,
 3. —OOH, or 4.—C(O)—NH—C₃-C₆cycloalkyl.
 17. A compound according to claim 16, or apharmaceutrically acceptable salt thereof wherein: R₃ is hydrogen. 18.The compound according to claim 1, selected from the group consistingof:8-(3-{2-(3-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-[4-(methylsulfonyl)phenyl]-2-(1-oxidopyridin-4-yl)-1,3-thiazol-5-yl]phenyl}quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[4-[4-(methylsulfonyl)phenyl]-2-(1-oxidopyridin-3-yl)-1,3-thiazol-5-yl]phenyl}quinoline,2-(3-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}phenyl)propan-2-ol,3-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}benzoicacid,2-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,N-cyclopropyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazole-2-carboxamide,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-(6-methyl-1-oxidopyridin-3-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)quinoline,2-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-methyl-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}phenyl)quinoline,2-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}propan-2-ol,1,1,1-trifluoro-N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}methanesulfonamide,2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-pyridin-3-yl-1,3-thiazol-2-yl]propan-2-ol,2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-(1-oxidopyridin-3-yl)-1,3-thiazol-2-yl]propan-2-ol,1-(4-chlorophenyl)-1-{4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}ethanol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]thien-2-yl}phenyl)quinoline,1-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)ethanone,2-(3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-yl)propan-2-ol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-oxidopyridin-3-yl]phenyl}quinoline,5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6-[4-(methylsulfonyl)phenyl]imidazo[2,1-b][1,3]thiazol-5-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]imidazo[1,2-a]pyridin-3-yl}phenyl)quinoline[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylthio)-1,1′:2′,1″-terphenyl-4′-yl]methanol,[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]methanol,2-[3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-yl]propan-2-ol,3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-carboxylicacid,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,8-{3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline,3″-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′:2′,1″-terphenyl-4-carboxylicacid,2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylsulfonyl)phenyl]pyrazin-2-yl}phenyl)quinoline,5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,1-methyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,8-(3-{6-methoxy-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-(3-{6-(difluoromethoxy)-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-(3-{6-[(4-fluorobenzyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,1-(4-fluorobenzyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-6-[4-(methylsulfonyl)phenyl]pyridin-2(1H)-one,5-(4-fluorophenyl)-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one,5-(4-fluorophenyl)-1-methyl-6-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one,8-{3-[3-(4-fluorophenyl)-6-methoxypyridin-2-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, of formula Ia:

wherein R is selected from the group consisting of Amino 2-biphenyl3-biphenyl N-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-ylN-(tert-butoxycarbonyl)azetidin-3-ylN-(tert-butoxycarbonyl)pyrrolidin-3-yl 3-chloro-4-fluorophenyl4-chlorophenoxymethyl 2-chlorophenyl 4-chlorophenyl Ethoxycarbonylfuran-2-yl furan-3-yl imidazol-2-yl indan-1-yl indan-2-yl 1H-indol-2-yl1H-indol-3-yl 1H-indol-4-yl 1H-indol-5-yl 1H-indol-6-yl 1H-indol-7-ylIsoquinolin-1-yl Isoquinolin-4-yl Isoquinolin-5-yl lsoquinolin-8-ylisoxazol-3-yl 3-methoxycarbonylphenyl 4-methoxycarbonylphenyl Methyl1-methyl-1H-pyrazol-3-yl 1-methyl-1H-pyrazol-4-yl1-methyl-1H-pyrazol-5-yl 2-methylphenyl 3-methylphenyl 4-methylphenyl2-methylpyridin-5-yl Methylsulfonylmethyl 2-methylsulfonylphenyl3-methylsulfonylphenyl 4-methylsulfonylphenyl morpholin-4-ylmethylPhenyl Pyrazinyl 1H-pyrazol-3-yl pyridin-2-yl pyridin-3-yl pyridin-4-yl3-pyridinylmethyl pyrimidin-2-yl pyrimidin-4-yl pyrimidin-5-ylquinolin-4-yl quinolin-5-yl quinolin-8-yl5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl6,7,8,9-tetrahydro-5H-benzo[a][7]annulen-5-yl6,7,8,9-tetrahydro-5H-benzo[a][7]annulen-6-yl Tetrahydrofuran-2-yl1,2,3,4-tetrahydronaphthalen-1-yl 1,2,3,4-tetrahydronaphthalen-2-yl1,3-thiazol-2-yl 1,3-thiazol-5-yl thiophen-2-yl thiophen-3-yl


20. The compound according to claim 1, selected from the groupconsisting of:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[3-(methylsulfonyl)phenyl]-4-phenyl-1,3-thiazol-5-yl}phenyl)quinoline,2-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,2-[4-(4-fluorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,8-{3-[4-(4-chlorophenyl)-2-quinolin-5-yl-1,3-thiazol-5-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,2-{3-[4-(3-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,2-{3-[4-(3-chloro-4-fluorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,2-{3-[4-[3,4-bis(difluoromethoxy)phenyl]-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide,N-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}pyridin-4-amine,2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-pyridin-4-yl-1,3-thiazol-2-yl]propan-2-ol,2-[5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-(1-oxidopyridin-4-yl)-1,3-thiazol-2-yl]propan-2-ol,2-[5-(4-chlorophenyl)-4-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]propan-2-ol,2-{3-[4-(4-chlorophenyl)-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-1,3-thiazol-2-yl]phenyl}propan-2-ol,and6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(1H-tetraazol-5-yl)pyridin-3-yl]phenyl}quinoline,or a pharmaceuticaly acceptable salt thereof.
 21. The compound accordingto claim 1, selected from the group consisting of:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[3-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[2-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{2-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3-(1-oxido-5-phenylpyridin-3-yl)phenyl]quinoline,8-{3-[5-(3,5-dichlorophenyl)-1-oxidopyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-{3-[5-(3,4-dimethoxyphenyl)-1-oxidopyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxidopyridin-3-yl]phenyl}quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[5-(5-methyl-1,3,4-oxadiazol-2yl)-1-oxidopyridin-3-yl]phenyl}quinoline,8-{3-[6-(benzyloxy)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{6-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-{3-[3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-2-yl]phenyl}quinoline,1-(4-chlorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyridin-2(1H)-one,N-isopropyl-5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:2′,1″-terphenyl-3-yl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[4″-(methylthio)-1,1′:2′,1″-terphenyl-3-yl]quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[2′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-yl]quinoline,methyl3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-4′-carboxylate,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:4′,1″-terphenyl-3-yl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(1,1′:3′,1″-terphenyl-3-yl)quinoline,2-[5-(3′-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}-1,1′-biphenyl-2-yl)-1,3-thiazol-2-yl]propan-2-ol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-[3′-(1-oxidopyridin-4-yl)-1,1′-biphenyl-3-yl]quinoline,or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim 1, selected from the group consisting of:6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]pyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-3-yl}phenyl)quinoline,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{4-[3-(methylthio)phenyl]pyridin-3-yl}phenyl)quinoline,8-[4′,5″-difluoro-4″-(methylthio)-1,1′:2′,1″-terphenyl-3-yl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-[4′,5′-difluoro-4″-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3-yl]-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-(4″-fluoro-1,1′:2′,1″-terphenyl-3-yl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,6,7-dichloro-2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-[4-(methylsulfonyl)phenyl]quinoxaline,2-(4-chlorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,2-{4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]phenyl}propan-2-ol,2-[3,4-bis(difluoromethoxy)phenyl]-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]benzoicacid,N-cyclopropyl-4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxalin-2-yl]benzamide,2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-(4-methylphenyl)quinoxaline,2-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-3-phenylquinoxaline,2-(4-fluorophenyl)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)quinoxaline,2-{4-[3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)pyrazin-2-yl]phenyl}propan-2-ol,6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{3-[4-(methylthio)phenyl]pyrazin-2-yl}phenyl)quinoline,8-{3-[3-(4-fluorophenyl)pyrazin-2-yl]phenyl}-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,8-(3-{2-(2-ethylpyridin-4-yl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}phenyl)-6-[1-methyl-1-(methylsulfonyl)ethyl]quinoline,2-(4-{5-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]quinolin-8-yl}phenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}phenyl)propan-2-ol,or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 24. Thepharmaceutical composition according to claim 18, further comprising aLeukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor,an M2/M3 antagonist, a corticosteroid, an H1 receptor antagonist or abeta 2 adrenoceptor agonist.
 25. The pharmaceutical compositionaccording to claim 18, further comprising a COX-2 selective inhibitor, astatin, or an NSAID.
 26. A method of treatment or prevention of asthma;chronic bronchitis; chronic obstructive pulmonary disease; adultrespiratory distress syndrome; infant respiratory distress syndrome;cough; chronic obstructive pulmonary disease in animals; adultrespiratory distress syndrome; ulcerative colitis; Crohn's disease;hypersecretion of gastric acid; bacterial, fungal or viral inducedsepsis or septic shock; endotoxic shock; laminitis or colic in horses;spinal cord trauma; head injury; neurogenic inflammation; pain;reperfusion injury of the brain; psoriatic arthritis; rheumatoidarthritis; ankylosing spondylitis; osteoarthritis; inflammation; orcytokine-mediated chronic tissue degeneration comprising the step ofadministering a therapeutically effective amount, or a prophylacticallyeffective amount, of the compound according to claim 1 or apharmaceutically acceptable salt thereof.
 27. A method of treatment orprevention of allergic rhinitis, allergic conjunctivitis, eosinophilicgranuloma, osteoporosis, arterial restenosis, atherosclerosis,reperfusion injury of the myocardium chronic glomerulonephritis, vernalconjunctivitis, cachexia, transplant rejection, or graft versus hostdisease, comprising the step of administering a therapeuticallyeffective amount, or a prophylactically effective amount, of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 28. A method of treatment or prevention of depression, memoryimpairment, monopolar depression, Parkinson disease, Alzheimer'sdisease, acute and chronic multiple sclerosis, psoriasis, benign ormalignant proliferative skin diseases, atopic dermatitis, urticaria,cancer, tumor growth or cancerous invasion of normal tissues, comprisingthe step of administering a therapeutically effective amount, or aprophylactically effective amount, of the compound according to claim 1or a pharmaceutically acceptable salt thereof. 29-32. (canceled)